Inhibitors of bruton&#39;s tyrosine kinase and method of their use

ABSTRACT

The present disclosure is directed to compounds of formula I′ and methods of their use and preparation, as well as compositions comprising compounds of formula I′.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.62/265,780, filed on Dec. 10, 2015, which is incorporated herein byreference in its entirety.

TECHNICAL FIELD

The present disclosure is directed to small molecule tyrosine kinaseinhibitors.

BACKGROUND

Rheumatoid arthritis (“RA”) is a chronic, autoimmune, inflammatorydisorder that affects the lining of the joints, causing painful swellingthat can result in bone erosion and joint deformation. RA presents asignificant societal impact—it has a relatively high prevalence (about1% of the United States population suffers from RA), producesirreversible joint damage, and has a widespread occurrence ofco-morbities. While many patients benefit from currently marketedbiologic and small molecule medicines, most patients still suffered fromthe chronic pain and inflammation of the disease.

Cancer, in particular mantle cell lymphoma, chronic lymphocyticleukemia, macroglobulinemia, and multiple myeloma, continues to afflictpatients. Alternative, effective treatments of cancer are still needed.

Human Bruton's tyrosine kinase (“Btk”) is a ˜76 kDa protein belonging tothe Tec family of non-receptor tyrosine kinases. Tec kinases form thesecond largest family of cytoplasmic tyrosine kinases in mammaliancells, which consists of four other members in addition to BTK: theeponymous kinase TEC, ITK, TXK/RLK and BMX. Tec kinases areevolutionarily conserved throughout vertebrates. They are related to,but structurally distinct from, the larger Src and Syk kinase families.Tec family proteins are abundantly expressed in hematopoietic tissuesand play important roles in the growth and differentiation of blood andendothelial cells in mammals.

Based upon Btk expression from IHC studies described in the art, Btkinhibition has the potential to modulate biology associated with Bcells, macrophages, mast cells, osteoclasts, and plateletmicroparticles. Cometh, O. B., et al. Curr. Top. Microbiol. Immunol. BTKSignaling in B Cell Differentiation and Autoimmunity. 2015 Sep. 5. Therole of B cells in RA is supported by the therapeutic benefit exhibitedin the clinic upon B cell depletion with Rituximab™. Since auto-reactiveantibodies play such a critical role in synovial inflammation,therapeutic modulation of the B cell compartment is an attractivemechanism to treat early RA and potentially modulate disease at theearliest stages. B cell depletion in murine models such ascollagen-induced arthritis (CIA) prevents arthritis development.Svensson, et al. (1998) B cell-deficient mice do not develop type IIcollagen-induced arthritis (CIA). Clin Exp Immunol 111, 521-526.

Use of Btk inhibitors in preclinical models support the role of Btk in Bcell biology associated with RA. Btk inhibitors block antigenreceptor-induced signaling at the earliest stages and subsequent B cellproliferation. In addition, critical aspects of antigen presentationfunction, such as antigen internalization and upregulation ofco-stimulation molecules such as CD80 and CD86 and MHC-IIs can beblocked with Btk inhibitors (Kenny, E. F., et al. (2013) PLoS One 8,e74103). Btk inhibitors exhibit efficacy in a variety of rodentarthritis models, whether dosed prophylactically or fullytherapeutically (Di Paolo, J. A., et al. Nat Chem Biol (2011) 7, 41-50;Liu, L., et al. (2011) J Pharmacol Exp Ther 338, 154-163; Honigberg, L.A., et al. (2010) Proc Natl Acad Sci USA 107, 13075-13080; Evans, E. K.,et al. (2013) J Pharmacol Exp Ther 346, 219-228). In addition toameliorating disease symptoms, Btk inhibition decreases autoantibodyproduction and isotype switching, as well as epitope spreading frombovine collagen to rodent collagen. In addition, Btk inhibition showssignificant reductions in inflammation scores as assessed by inflamedpaw histopathology. Together, these data provide a rationale for testingBtk inhibitors in inflammatory autoimmune disorders where B cells play amajor role. In addition, Btk is a clinically validated target for thetreatment of hematological malignancies, with the irreversible covalentinhibitor (ICI) ibrutinib approved for treatment of B cell malignanciessuch as mantle cell lymphoma, chronic lymphocytic leukemia (CLL) andWaldenström's macroglobulinemia (Hendriks, R. W., et al. (2014) Nat RevCancer 14, 219-232).

In view of Btk's role in a variety of immunological and oncologicalpathways, inhibitors of Btk are needed.

SUMMARY

The present disclosure is directed to compounds of formula I:

-   wherein-   R¹ is H or C₁₋₆alkyl;-   R² is —C₀₋₆alk-piperidinyl; —C₀₋₆alk-pyrrolidinyl;    —C₀₋₆alk-oxazepanyl; —C₀₋₆alk-azetidinyl; —C₀₋₆alk-aziridinyl;    —C₀₋₆alk-azepanyl; —C₀₋₆alk-quinuclidinyl; —C₀₋₆alk-imidazolidinyl;    —C₀₋₆alk-piperazinyl; —C₀₋₆alkmorpholinyl;    —C₀₋₆alk-tetrahydropyranyl; or —C₀₋₆alk-tetrahydrofuranyl wherein    the R² is optionally substituted with 1, 2, or 3 substituents    independently selected from the group consisting of    -   —NR⁸—C(O)—C(R³)═CR⁴(R⁵); —C(O)—C(R³)═CR⁴(R⁵); oxo; halogen; —CN;        —OH; —NR⁶R⁷; —C₁₋₆alkyl; —C₁₋₆alk-OH; —OC₁₋₆alkyl;        —C₃₋₆cycloalkyl; —C₁₋₆haloalkyl; —C₁₋₆alkaryl; —SO₂—C₁₋₆alkyl;        —SO₂—C₂₋₆alkenyl; —C(O)H; —C(O)—C₁₋₆alkyl; —C(O)—C₃₋₆cycloalkyl;        —C(O)—C₁₋₆haloalkyl; —C(O)—C₂₋₆alkynyl; —C(O)—C₆₋₁₀aryl;        —C(O)-heteroaryl; —C(O)—C₁₋₆alk-CN; —C(O)—C₁₋₆alk-OH;        —C(O)—C₁₋₆alk-SO₂—C₁₋₆alkyl; —C(O)—O—C₁₋₆alkyl;        —C(O)—C₁₋₆alk-NR⁶R⁷; —C(O)—C₁₋₆alk-O—C₁₋₆alkyl wherein the        —C₁₋₆alk- is optionally substituted with —OH, —OC₁₋₆alkyl, or        —NR⁶R⁷; and —C(O)—C₀₋₆alk-heterocycloalkyl wherein the-alk- is        optionally substituted with oxo and the heterocycloalkyl is        optionally substituted with —C₁₋₆alkyl; wherein        -   R³ is H; —CN; halogen; —C₁₋₆haloalkyl; or —C₁₋₆alkyl;            -   R⁴ and R⁵ are each independently H; halogen; —C₁₋₆alkyl;                —OC₁₋₆alkyl; —C₀₋₆alk-C₃₋₆cycloalkyl optionally                substituted with C₁₋₆alkyl; —C₀₋₆alk-heterocycloalkyl                optionally substituted with —C(O)C₁₋₆alkyl or                —C₁₋₆alkyl; —C₁₋₆alk-OH; —C₀₋₆alk-NR⁶R⁷;                —C₁₋₆alk-O—C₁₋₆alkyl; —C₁₋₆alk-NH—C₀₋₆alk-O—C₁₋₆alkyl;                —C₁₋₆alk-NHSO₂—C₁₋₆alkyl; —C₁₋₆alk-SO₂—C₁₋₆alkyl;                —NHC(O)—C₁₋₆alkyl; or -linker-PEG-Biotin; and            -   R⁶ and R⁷ are each independently H; —C₁₋₆alkyl;                —C₃₋₆cycloalkyl; C(O)H, or —CN; and            -   R⁸ is H or C₁₋₆alkyl;-   A is a bond, pyridyl; phenyl; napthalenyl; pyrimidinyl; pyrazinyl;    pyridazinyl; benzo[d][1,3]dioxolyl optionally substituted with    halogen; benzothiophenyl; or pyrazolyl; optionally substituted with    1, 2, or 3 substituents independently selected from the group    consisting of —C₁₋₆alkyl; halogen; —SF₅; —OC₁₋₆alkyl;    —C(O)—C₁₋₆alkyl; and —C₁₋₆haloalkyl;-   E is —O—; a bond; —C(O)—NH—; —CH₂—; or —CH₂—O—;-   G is H; —C₃₋₆cycloalkyl; -phenyl; -thiophenyl; —C₁₋₆alkyl;    -pyrimidinyl; -pyridyl; -pyridazinyl; -benzofuranyl; —C₁₋₆haloalkyl;    -heterocycloalkyl that contains an oxygen heteroatom;    -phenyl-CH₂—O-phenyl; —C₁₋₆alk-O—C₁₋₆alkyl; —NR⁶R⁷; —SO₂C₁₋₆alkyl;    or —OH; wherein the phenyl; thiophenyl; pyrimidinyl; pyridyl;    pyridazinyl; or benzofuranyl is optionally substituted with 1, 2, or    3 substituents independently selected from the group consisting of    halogen; —C₁₋₆alkyl; —C₁₋₆haloalkyl; —OC₁₋₆haloalkyl;    —C₃₋₆cycloalkyl; —OC₁₋₆alkyl; —CN; —OH; —C₁₋₆alk-O—C₁₋₆alkyl;    —C(O)—NR⁶R⁷; and —C(O)—C₁₋₆alkyl;    -   or a stereoisomer or isotopic variant thereof,    -   or a pharmaceutically acceptable salt thereof.

Compositions comprising compounds of formula I are also described.Methods of using compounds of formula I are also within the scope of thedisclosure.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The disclosure may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. It is to be appreciated that certain features ofthe disclosed compositions and methods which are, for clarity, describedherein in the context of separate aspects, may also be provided incombination in a single aspect. Conversely, various features of thedisclosed compositions and methods that are, for brevity, described inthe context of a single aspect, may also be provided separately or inany subcombination.

The term “alkyl,” when used alone or as part of a substituent group,refers to a straight- or branched-chain alkyl group having from 1 to 12carbon atoms (“C₁₋₁₂”), preferably 1 to 6 carbons atoms (“C₁₋₆”), in thechain. Examples of alkyl groups include methyl (Me, C₁alkyl) ethyl (Et,C₂alkyl), n-propyl (C₃alkyl), isopropyl (C₃alkyl), butyl (C₄alkyl),isobutyl (C₄alkyl), sec-butyl (C₄alkyl), tert-butyl (C₄alkyl), pentyl(C₅alkyl), isopentyl (C₅alkyl), tert-pentyl (C₅alkyl), hexyl (C₆alkyl),isohexyl (C₆alkyl), and groups that in light of the ordinary skill inthe art and the teachings provided herein would be considered equivalentto any one of the foregoing examples.

When a range of carbon atoms is used herein, for example, C₁₋₆, allranges, as well as individual numbers of carbon atoms are encompassed.For example, “C₁₋₃” includes C₁₋₃, C₁₋₂, C₂₋₃, C₁, C₂, and C₃.

The term “C₁₋₆alk” refers to an aliphatic linker having 1, 2, 3, 4, 5,or 6 carbon atoms and includes, for example, —CH₂—, —CH(CH₃)—,—CH(CH₃)—CH₂—, and —C(CH₃)₂—. The term “—C₀alk-” refers to a bond. Insome aspects, the C₁₋₆alk can be substituted with an oxo group or an —OHgroup.

The term “alkenyl,” when used alone or as part of a substituent group,refers to straight and branched carbon chains having from 2 to 12 carbonatoms (“C₂₋₁₂”), preferably 2 to 6 carbon atoms (“C₂₋₆”), wherein thecarbon chain contains at least one, preferably one to two, morepreferably one double bond. For example, alkenyl moieties include, butare not limited to allyl, 1-propen-3-yl, 1-buten-4-yl,propa-1,2-dien-3-yl, and the like.

The term “alkynyl,” when used alone or as part of a substituent group,refers to straight and branched carbon chains having from 2 to 12 carbonatoms (“C₂₋₁₂”), preferably 2 to 6 carbon atoms (“C₂₋₆”), wherein thecarbon chain contains at least one, preferably one to two, morepreferably one triple bond. For example, alkynyl moieties include, butare not limited to vinyl, 1-propyn-3-yl, 2-butyn-4-yl, and the like.

The term “aryl” refers to carbocylic aromatic groups having from 6 to 10carbon atoms (“C₆₋₁₀”) such as phenyl, naphthyl, and the like.

The term “cycloalkyl” refers to monocyclic, non-aromatic hydrocarbongroups having from 3 to 10 carbon atoms (“C₃₋₁₀”), preferably from 3 to6 carbon atoms (“C₃₋₆”). Examples of cycloalkyl groups include, forexample, cyclopropyl (C₃), cyclobutyl (C₄), cyclopentyl (C₅), cyclohexyl(C₆), 1-methylcyclopropyl (C₄), 2-methylcyclopentyl (C₄), adamantanyl(C₁₀), and the like.

The term “heterocycloalkyl” refers to any five to ten memberedmonocyclic or bicyclic, saturated ring structure containing at least oneheteroatom selected from the group consisting of O, N and S. Theheterocycloalkyl group may be attached at any heteroatom or carbon atomof the ring such that the result is a stable structure. Examples ofsuitable heterocycloalkyl groups include, but are not limited to,azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl,imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl,quinuclidinyl, tetrahyofuranyl, tetrahydropyranyl, piperazinyl,hexahydro-5H-[1,4]dioxino[2,3-c]pyrrolyl, benzo[d][1,3]dioxolyl, and thelike.

The term “heteroaryl” refers to a mono- or bicyclic aromoatic ringstructure including carbon atoms as well as up to four heteroatomsselected from nitrogen, oxygen, and sulfur. Heteroaryl rings can includea total of 5, 6, 9, or 10 ring atoms (“C₅₋₁₀”). Examples of heteroarylgroups include but are not limited to, pyrrolyl, furyl, thiophenyl(thienyl), oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl,triazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl,indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl,purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,pteridinyl, and the like.

The term “halogen” represents chlorine, fluorine, bromine, or iodine.The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “haloalkyl” refers to an alkyl moiety wherein one or more ofthe hydrogen atoms has been replaced with one or more halogen atoms. Oneexemplary substitutent is fluoro. Preferred haloalkyl groups of thedisclosure include trihalogenated alkyl groups such as trifluoromethylgroups.

The term “oxo” refers to a ═O moiety, wherein two hydrogens from thesame carbon atom have be replaced with a carbonyl. For example, anoxo-substituted pyrrolidinyl moiety could be a pyrrolidin-2-one moietyor a pyrrolidin-3-one moiety.

The term “benzofuranyl” represents the following moiety:

The benzofuranyl moiety can be attached through any one of the 2-, 3-,4-, 5-, 6-, or 7-carbon atoms.

The term “benzo[d][1,3]dioxolyl” represents the following moiety:

The benzo[d][1,3]dioxolyl moiety can be attached through any one of the2-, 4-, 5-, 6-, or 7-carbon atoms. In those aspects wherein the“benzo[d][1,3]dioxolyl moiety is substituted with halogen,” thefollowing moieties are preferred:

The term “benzothiophenyl” represents the following moiety:

The benzothiophenyl moiety can be attached through any one of the 2-,3-, 4-, 5-, 6-, or 7-carbon atoms.

The term “phenyl” represents the following moiety:

The phenyl moiety can be attached through any of the carbon atoms.

The term “napthalenyl” (i.e., naphthyl) represents the following moiety:

The naphthalenyl moiety can be attached through any one of the 1-, 2-,3-, 4-, 5-, 6-, 7-, or 8-position carbon atoms.

The term “pyridyl” represents the following moiety:

The pyridyl moiety can b attached through any one of the 2-, 3-, 4-, 5-,or 6-position carbon atoms.

The term “pyrimidinyl” represents the following moiety:

The pyrimidinyl moiety can be attached through any one of the 2-, 4-,5-, or 6-position carbon atoms.

The term “pyrazinyl” represents the following moiety:

The pyrazinyl moiety can be attached through any one of the 2-, 3-, 5-,or 6-position carbon atoms.

The term “pyridazinyl” represents the following moiety:

The pyridazinyl moiety can be attached through any one of the 3-, 4-,5-, or 6-position carbon atoms.

The term “pyrazolyl” represents the following moiety:

The pyrazolyl moiety can be attached through any one of the 1-, 2-, 3-,4-, or 5-position carbon atoms.

The term “thiophenyl” represents the following moiety:

The thiophenyl moiety can be attached through any one of the 2-, 3-, 4-,or 5-position carbon atoms.

The term “linker-PEG-Biotin” refers to a moiety comprising

linker-PEG-CH₂—NH-biotinyl. Compounds of the disclosure that include alinker-PEG-Biotin moiety can be used according to any of the methodsdescribed herein. Alternatively, compounds of the disclosure thatinclude a linker-PEG-Biotin moiety can be used as diagnostic probesaccording to methods known in the art. Preferred linkers are known inthe art, with the linker —CH₂—NHC(O)—(CH₂)₃—C(O)—NH—CH₂— beingparticularly preferred. Preferred PEG moieties include at least two orthree repeating —CH₂—CH₂—O— moieties. A preferred linker-PEG-Biotinmoiety is

The term “piperidinyl” represents the following moiety:

Within the disclosure, when R² is a C₀alk-piperidinyl moiety, it can beattached to the compound of formula I through any one of the 2-, 3-, 4-,5-, or 6-position atoms. In other aspects, when R² is aC₀alk-piperidinyl moiety, it can be attached to the compound of formulaI through any ring atom. Within the disclosure, when R² is aC₁₋₆alk-piperidinyl moiety, it can be attached to the compound offormula I through any one of the 1-, 2-, 3-, 4-, 5-, or 6-positionatoms. When the piperidinyl moiety is a substituent, it can be attachedthrough any one of the 1-, 2-, 3-, 4-, 5-, or 6-position atoms.

The term “pyrrolidinyl” represents the following moiety:

Within the disclosure, when R² is a C₀alk-pyrrolidinyl moiety, it can beattached to the compound of formula I through any one of the 2-, 3-, 4-,or 5-position atoms. In other aspects, when R² is a C₀alk-pyrrolidinylmoiety, it can be attached to the compound of formula I through any ringatom. Within the disclosure, when R² is a C₁₋₆alk-pyrrolidinyl moiety,it can be attached to the compound of formula I through any one of the1-, 2-, 3-, 4-, or 5-position atoms. When the pyrrolidinyl moiety is asubstituent, it can be attached through any one of the 1-, 2-, 3-, 4-,or 5-position atoms.

The term “oxazepanyl” refers to a 7-membered heterocycloalkyl moietyhaving one ring nitrogen atom and one ring oxygen atom. Examples include1,3-oxazepanyl and 1,4-oxazepanyl moieties

Within the disclosure, when R² is a C₀alk-oxazepanyl moiety, it can beattached to the compound of formula I through any one of the ring carbonatoms. In other aspects, when R² is a C₀alk-oxazepanyl moiety, it can beattached to the compound of formula I through any ring nitrogen orcarbon atom. Within the disclosure, when R² is a C₁₋₆alk-oxazepanylmoiety, it can be attached to the compound of formula I through any oneof the ring carbon atoms or nitrogen ring atom. When the oxazepanylmoiety is a substituent, it can be attached through any ring carbon atomor through the nitrogen atom.

The term “aziridinyl” represents a 3-membered heterocycloalkyl moietyhaving one ring nitrogen. Within the disclosure, when R² is aC₀alk-aziridinyl moiety, it can be attached to the compound of formula Ithrough any one of the ring carbon atoms. In other aspects, when R² is aC₁₋₆alk-aziridinyl moiety, it can be attached to the compound of formulaI through any one of the ring carbon atoms or the nitrogen ring atom.When the aziridinyl moiety is a substituent, it can be attached throughany carbon atom or through the nitrogen atom.

The term “azetidinyl” represents a 4-membered heterocycloalkyl moietyhaving one ring nitrogen. Within the disclosure, when R² is anC₀alk-azetidinyl moiety, it can be attached to the compound of formula Ithrough any one of the ring carbon atoms. In other aspects, when R² is aC₁₋₆alk- azetidinyl moiety, it can be attached to the compound offormula I through any one of the ring carbon atoms or the nitrogen ringatom. Within the disclosure, when R² is an C₁₋₆alk-azetidinyl moiety, itcan be attached to the compound of formula I through any one of the ringcarbon atoms or the nitrogen ring atom. When the azetidinyl moiety is asubstituent, it can be attached through any carbon atom or through thenitrogen atom.

The term “azepanyl” represents a 7-membered heterocycloalkyl moietyhaving one ring nitrogen. Within the disclosure, when R² is anC₀alk-azepanyl moiety, it can be attached to the compound of formula Ithrough any one of the ring carbon atoms. In other aspects, when R² is aC₁₋₆alk-azepanyl moiety, it can be attached to the compound of formula Ithrough any one of the ring carbon atoms or the nitrogen ring atom.Within the disclosure, when R² is an C₁₋₆alk-azepanyl moiety, it can beattached to the compound of formula I through any one of the ring carbonatoms or nitrogen ring atom. When the azepanyl moiety is a substitutent,it can be attached through any carbon atom or through the nitrogen atom.

The term “quinuclidinyl” represents the following moiety:

Within the disclosure, when R² is a quinuclidinyl moiety, or when thequinuclidinyl moiety is a substituent, it can be attached to thecompound of formula I through any one of the ring carbon atoms.

The term “imidazolidinyl” represents the following moiety:

Within the disclosure, when R² is an C₀alk-imidazolidinyl moiety, it canbe attached to the compound of formula I through any one of the ringcarbon atoms. In other aspects, when R² is a C₁₋₆alk- imidazolidinylmoiety, it can be attached to the compound of formula I through any oneof the ring carbon atoms or the nitrogen ring atom. Within thedisclosure, when R² is an C₁₋₆alk-imidazolidinyl moiety, it can beattached to the compound of formula I through any one of the ring carbonatoms or any nitrogen ring atom. When the imidazolidinyl moiety is asubstituent, it can be attached through any one of the 1-, 2-, 3-, 4-,or 5-position atoms.

The term “piperazinyl” represents the following moiety:

Within the disclosure, when R² is a C₀alk-piperazinyl moiety, it can beattached to the compound of formula I through any one of the ring carbonatoms. In other aspects, when R² is a C₁₋₆alk-piperazinyl moiety, it canbe attached to the compound of formula I through any one of the ringcarbon atoms or the nitrogen ring atom. Within the disclosure, when R²is a C₁₋₆alk-piperazinyl moiety, it can be attached to the compound offormula I through any one of the ring carbon atoms or nitrogen ringatoms. When the piperazinyl moiety is a substituent, it can be attachedthrough any one of the 1-, 2-, 3-, 4-, 5-, or 6-position atoms.

The term “morpholinyl” represents the following moiety:

Within the disclosure, when R² is a C₀alk-morpholinyl moiety, it can beattached to the compound of formula I through any one of the ring carbonatoms. In other aspects, when R² is a C₁₋₆alk-morpholinyl moiety, it canbe attached to the compound of formula I through any one of the ringcarbon atoms or the nitrogen ring atom. Within the disclosure, when R²is a C₁₋₆alk-morpholinyl moiety, it can be attached to the compound offormula I through any one of the ring carbon atoms or nitrogen ringatom. When the morpholinyl moiety is a substituent, it can be attachedthrough any one of the 2-, 3-, 4-, 5-, or 6-position atoms.

The term “tetrahydropyranyl” represents a 6-membered heterocycloalkylmoiety having one ring oxygen. The tetrahydropyranyl moiety can beattached through any carbon atom on the ring.

The term “tetrahydrofuranyl” represents a 5-membered heterocycloalkylmoiety having one ring oxygen. The tetrahydrofuranyl moiety can beattached through any carbon atom on the ring.

As used hereing, the term “compound(s) of formula I” includes thosecompounds of “formula I,” as well as compounds of any of the formula Isubgenera.

Within the scope of the disclosure, solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and areformed during the process of product formation or isolation withpharmaceutically acceptable solvents such as water, ethanol, methanol,methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate,isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK),methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF),dichloromethane (DCM), dioxane, heptanes, toluene, anisole,acetonitrile, and the like. In one aspect, solvates are formed using,but not limited to, Class 3 solvent(s). Categories of solvents aredefined in, for example, the International Conference on Harmonizationof Technical Requirements for Registration of Pharmaceuticals for HumanUse (ICH), “Impurities: Guidelines for Residual Solvents, Q3C(R3)(November 2005) Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. In some embodimentssolvates of the described compounds, or pharmaceutically acceptablesalts thereof, are conveniently prepared or formed during the processesdescribed herein. In some embodiments, solvates of the compoundsdescribed herein are anhydrous. In some embodiments, the compoundsdescribed herein or pharmaceutically acceptable salts thereof, exist inunsolvated form. In some embodiments, the compounds described herein, orpharmaceutically acceptable salts thereof; exist in unsolvated form andare anhydrous.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of thedisclosure that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the disclosure isadministered. A “pharmaceutically acceptable excipient” refers to asubstance that is non-toxic, biologically tolerable, and otherwisebiologically suitable for administration to a subject, such as an inertsubstance, added to a pharmacological composition or otherwise used as avehicle, carrier, or diluent to facilitate administration of a agent andthat is compatible therewith. Examples of excipients include calciumcarbonate, calcium phosphate, various sugars and types of starch,cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

“Subject” includes humans. The terms “human,” “patient,” and “subject”are used interchangeably herein.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

“Compounds of the present disclosure,” and equivalent expressions, aremeant to embrace compounds of the Formula (I) as described herein, whichexpression includes the pharmaceutically acceptable salts, and thesolvates, e.g., hydrates, where the context so permits. Similarly,reference to intermediates, whether or not they themselves are claimed,is meant to embrace their salts, and solvates, where the context sopermits.

As used herein, the term “isotopic variant” refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound. For example, an “isotopic variant” of acompound can be radiolabeled, that is, contain one or morenon-radioactive isotopes, such as for example, deuterium (²H or D),carbon-13 (¹³C), nitrogen-15 (¹⁵N), or the like. It will be understoodthat, in a compound where such isotopic substitution is made, thefollowing atoms, where present, may vary, so that for example, anyhydrogen may be ²H/D, any carbon may be ¹³C, or any nitrogen may be ¹⁵N,and that the presence and placement of such atoms may be determinedwithin the skill of the art. Likewise, the disclosure may include thepreparation of isotopic variants with radioisotopes, in the instance forexample, where the resulting compounds may be used for drug and/orsubstrate tissue distribution studies. Radiolabeled compounds of thedisclosure can be used in diagnostic methods such as Single-photonemission computed tomography (SPECT). The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for their easeof incorporation and ready means of detection. Further, compounds may beprepared that are substituted with positron emitting isotopes, such as¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in Positron EmissionTopography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds of the disclosure, radioactive ornot, are intended to be encompassed within the scope of the disclosure.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers,” for example, diastereomers, enantiomers, andatropisomers.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers.” When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture.”

“Atropisomers” refer to stereoisomers that arise because of hinderedrotation around a single bond.

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenyl nitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

The compounds of this disclosure may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof.Within the present disclosure, any open valency appearing on a carbon,oxygen, or nitrogen atom in any structure described herein indicates thepresence of a hydrogen atom. Where a chiral center exists in astructure, but no specific stereochemistry is shown for that center,both enantiomers, separately or as a mixture, are encompassed by thatstructure. The methods for the determination of stereochemistry and theseparation of stereoisomers are well-known in the art.

The present disclosure is directed to compounds of formula I:

wherein L is —C(O)NR¹—, —C₁₋₆alk-NR¹—, a bond, or —NR¹—C(O)—. Inpreferred embodiments, L is —C(O)NR¹—, corresponding to compounds offormula I′:

In other aspects, L is —C₁₋₆alk-NR¹—, corresponding to compounds offormula I″:

In other aspects, L is a bond, corresponding to compounds of formulaI′″:

In other aspects, L is —NR—C(O)—, corresponding to compounds of formulaI″″:

A preferred embodiment of the disclosure is a compound of Formula (I)having the Formula (I′):

-   wherein-   R¹ is H or C₁₋₆alkyl;-   R² is —C₀₋₆alk-piperidinyl; —C₀₋₆alk-pyrrolidinyl;    —C₀₋₆alk-oxazepanyl; —C₀₋₆alk-azetidinyl; —C₀₋₆alk-aziridinyl;    —C₀₋₆alk-azepanyl; —C₀₋₆alk-quinuclidinyl; —C₀₋₆alk-imidazolidinyl;    —C₀₋₆alk-piperazinyl; —C₀₋₆alkmorpholinyl;    —C₀₋₆alk-tetrahydropyranyl; or —C₀₋₆alk-tetrahydrofuranyl wherein    the R² is optionally substituted with 1, 2, or 3 substituents    independently selected from the group consisting of    -   —NR—C(O)—C(R³)═CR⁴(R⁵); —C(O)—C(R³)═CR⁴(R⁵); oxo; halogen; —CN;        —OH; —NR⁶R⁷; —C₁₋₆alkyl; —C₁₋₆alk-OH; —OC₁₋₆alkyl;        —C₃₋₆cycloalkyl; —C₁₋₆haloalkyl; —C₁₋₆alkaryl; —SO₂—C₁₋₆alkyl;        —SO₂—C₂₋₆alkenyl; —C(O)H; —C(O)—C₁₋₆alkyl; —C(O)—C₃₋₆cycloalkyl;        —C(O)—C₁₋₆haloalkyl; —C(O)—C₂₋₆alkynyl; —C(O)—C₆₋₁₀aryl;        —C(O)-heteroaryl; —C(O)—C₁₋₆alk-CN; —C(O)—C₁₋₆alk-OH;        —C(O)—C₁₋₆alk-SO₂—C₁₋₆alkyl; —C(O)—O—C₁₋₆alkyl;        —C(O)—C₁₋₆alk-NR⁶R⁷; —C(O)—C₁₋₆alk-O—C₁₋₆alkyl wherein the        —C₁₋₆alk- is optionally substituted with —OH, —OC₁₋₆alkyl, or        —NR⁶R⁷; and —C(O)—C₀₋₆alk-heterocycloalkyl wherein the -alk- is        optionally substituted with oxo and the heterocycloalkyl is        optionally substituted with —C₁₋₆alkyl; wherein        -   R³ is H; —CN; halogen; —C₁₋₆haloalkyl; or —C₁₋₆alkyl;            -   R⁴ and R⁵ are each independently H; halogen; —C₁₋₆alkyl;                —OC₁₋₆alkyl; —C₀₋₆alk-C₃₋₆cycloalkyl optionally                substituted with C₁₋₆alkyl; —C₀₋₆alk-heterocycloalkyl                optionally substituted with —C(O)C₁₋₆alkyl or                —C₁₋₆alkyl; —C₁₋₆alk-OH; —C₀₋₆alk-NR⁶R⁷;                —C₁₋₆alk-O—C₁₋₆alkyl; —C₁₋₆alk-NH—C₀₋₆alk-O—C₁₋₆alkyl;                —C₁₋₆alk-NHSO₂—C₁₋₆alkyl; —C₁₋₆alk-SO₂—C₁₋₆alkyl;                —NHC(O)—C₁₋₆alkyl; or -linker-PEG-Biotin; and            -   R⁶ and R⁷ are each independently H; —C₁₋₆alkyl;                —C₃₋₆cycloalkyl; C(O)H, or —CN; and            -   R⁸ is H or C₁₋₆alkyl;-   A is a bond, pyridyl; phenyl; napthalenyl; pyrimidinyl; pyrazinyl;    pyridazinyl; benzo[d][1,3]dioxolyl optionally substituted with    halogen; benzothiophenyl; or pyrazolyl; optionally substituted with    1, 2, or 3 substituents independently selected from the group    consisting of —C₁₋₆alkyl; halogen; —SF₅; —OC₁₋₆alkyl;    —C(O)—C₁₋₆alkyl; and —C₁₋₆haloalkyl;-   E is —O—; a bond; —C(O)—NH—; —CH₂—; or —CH₂—O—; and-   G is H; —C₃₋₆cycloalkyl; -phenyl; -thiophenyl; —C₁₋₆alkyl;    -pyrimidinyl; -pyridyl; -pyridazinyl; -benzofuranyl; —C₁₋₆haloalkyl;    -heterocycloalkyl that contains an oxygen heteroatom;    -phenyl-CH₂—O-phenyl; —C₁₋₆alk-O—C₁₋₆alkyl; —NR⁶R⁷; —SO₂C₁₋₆alkyl;    or —OH; wherein the phenyl; thiophenyl; pyrimidinyl; pyridyl;    pyridazinyl; or benzofuranyl is optionally substituted with 1, 2, or    3 substituents independently selected from the group consisting of    halogen; —C₁₋₆alkyl; —C₁₋₆haloalkyl; —OC₁₋₆haloalkyl;    —C₃₋₆cycloalkyl; —OC₁₋₆alkyl; —CN; —OH; —C₁₋₆alk-O—C₁₋₆alkyl;    —C(O)—NR⁶R⁷; and —C(O)—C₁₋₆alkyl.

Stereoisomers and isotopic variants of Formula I′ are also within thescope of the disclosure. Pharmaceutically acceptable salts of Formula I′are also within the scope of the disclosure.

The present disclosure is preferably directed to compounds of Formula(I′)

wherein

-   R¹ is H or C₁₋₆alkyl;-   R² is selected from the group consisting of: C₀₋₂alk-piperidinyl;    C₀₋₂alk-pyrrolidinyl; oxazepanyl; azetidinyl; azepanyl;    quinuclidinyl; C₂alk-imidazolidinyl; C₂alk-piperazinyl;    C₂alk-morpholinyl; tetrahydropyranyl; and C₀₋₁alk-tetrahydrofuranyl;    wherein the R² is optionally substituted with 1, 2, or 3    substituents each independently selected from the group consisting    of:    -   (C═O)—C(R³)═CR⁴(R⁵); oxo; halogen; OH; NH₂; CN; C₁₋₆alkyl;        C₁₋₆alk-OH; OC₁₋₆alkyl; C₁₋₆haloalkyl; C₃₋₆cycloalkyl;        SO₂C₁₋₆alkyl; SO₂—C₂₋₆alkenyl; C₁₋₂alk-aryl; (C═O)H;        (C═O)C₁₋₆alkyl; (C═O)C₁₋₆haloalkyl; (C═O)—C₂₋₆alkenyl;        (C═O)—C₂₋₆alkynyl; (C═O)C₃₋₆cycloalkyl; (C═O)-phenyl;        (C═O)-imidazolyl; (C═O)—C₁₋₆alkCN; (C═O)—C₁₋₆alk-OH;        (C═O)—C₁₋₆alk-SO₂C₁₋₆alkyl; (C═O)—C₁₋₆alk-NR⁶R⁷;        (C═O)—C₁₋₆alk-O—C₁₋₆alkyl wherein the —C₁₋₆alk- is optionally        substituted with OH, OC₁₋₆alkyl, or NR⁶R⁷;        (C═O)C₀₋₁alk-heterocycloalkyl wherein the -alk- is optionally        substituted with oxo and the heterocycloalkyl is optionally        substituted with C₁₋₆alkyl; and NH(C═O)—C(R³)═CR⁴(R⁵);    -   wherein        -   R³ is selected from the group consisting of: H, CN, halogen,            C₁₋₆haloalkyl, and C₁₋₆alkyl;        -   R⁴ and R⁵ are each independently selected from the group            consisting of: H; halogen; C₁₋₆alkyl; CH₂OH;            C₁₋₆alk-OC₁₋₆alkyl; OC₁₋₆alkyl; C₁₋₄alk-NR⁶R⁷;            C₃₋₆cycloalkyl substituted with NH₂ or CH₃; oxetanyl            substituted with CH₃; 1-acetylpyrrolidin-2-yl;            CH₂-pyrrolidinyl; CH₂-piperidinyl; C(CH₃)₂-piperidinyl;            CH₂-morpholinyl; C(CH₃)₂-morpholinyl;            CH₂-(4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl;            C(CH₃)₂NH(CH₂CH₂OCH₃); CH₂SO₂CH₃; CH₂NHSO₂CH₃;            NH(C═O)C₁₋₆alkyl; and linker-PEG-Biotin; and        -   R⁶ and R⁷ are each independently selected from the group            consisting of: H, C₁₋₆alkyl, cyclopropyl, (C═O)H, and CN;-   A is selected from the group consisting of: a bond, phenyl;    naphthalenyl, pyridyl; pyrimidinyl; pyrazinyl; pyridazinyl;    benzothiophenyl; and pyrazolyl; wherein the A is optionally    substituted with 1, 2, or 3 substituents each independently selected    from the group consisting of: C₁₋₆alkyl, halogen, OC₁₋₆alkyl,    (C═O)C₁₋₆alkyl, and C₁₋₆haloalkyl;-   E is selected from the group consisting of: —O—, a bond, (C═O)—NH,    CH₂, and CH₂—O; and-   G is selected from the group consisting of: H, C₁₋₆alkyl;    C₁₋₆haloalkyl; C₁₋₆alk-OC₁₋₆alkyl; NR⁶R⁷; SO₂C₁₋₆alkyl; OH;    C₃₋₆cycloalkyl; phenyl; thiophenyl; pyrimidinyl; pyridyl;    pyridazinyl; benzofuranyl; heterocycloalkyl that contains an oxygen    heteroatom; phenyl-CH₂—O-phenyl; wherein the phenyl, thiophenyl,    pyrimidinyl, pyridyl, pyridazinyl, or benzofuranyl is optionally    substituted with 1, 2, or 3 substituents each independently selected    from the group consisting of: halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,    OC₁₋₆haloalkyl, OC₁₋₆alkyl, OC₁₋₆alkyl-OC₁₋₆alkyl, C₃₋₆cycloalkyl,    CN, OH, NH₂, N(CH₃)₂, C₁₋₆alk-OC₁₋₆alkyl, SO₂C₁₋₆alkyl, (C═O)—NR⁶R⁷,    SF₅, and (C═O)C₁₋₆alkyl.

Stereoisomers and isotopic variants, pharmaceutically acceptable salts,N-oxides, and solvates of Formula I′ are also within the scope of thedisclosure.

An additional embodiment of the disclosure is directed to compounds ofFormula (II′), as well as the stereoisomers, isotopic variants, andpharmaceutically acceptable salt thereof:

-   -   wherein    -   R^(a) is independently selected from the group consisting of: H,        Cl, F, CH₃, and CF₃; n is 0-2;    -   E is O;    -   G is selected from the group consisting of: C₃₋₆cycloalkyl;        oxetanyl; tetrahydrofuranyl; tetrahydropyranyl;        benzofuran-7-yloxy; pyridyl; pyridyl substituted with CH₃;        phenyl; phenyl substituted with one or two members independently        selected from the group consisting of: halogen, C₁₋₆alkyl,        C₁₋₆haloalkyl, OH, OC₁₋₆alkyl, OC₁₋₆haloalkyl, CH₂OCH₃,        (C═O)NH₂, and C₃₋₆cycloalkyl; and

-   -   Ring B is selected from the group consisting of:        -   (a)

-   -    where R^(b) is selected from the group consisting of: H;        C₁₋₆alkyl, C₃₋₆cycloalkyl, (C═O)CH═CH₂, (C═O)CH₂CH₂OCH₃,        (C═O)CH₂CH₂SO₂CH₃, and

-   -   -   (b)

-   -   -   -   where R^(c) is selected from the group consisting of: H,                C₁₋₆alkyl, CN, (C═O)C₁₋₃alkyl, (C═O)CH═CH₂,                C₃₋₆cycloalkyl, (C═O)CH₂NH₂, (C═O)CH₂NH(CH₃),                (C═O)CH₂N(CH₃)₂, (C═O)CH₂CN, CH₂-phenyl, (C═O)CH₂Cl,                (C═O)CH═CHCH₂NH₂, (C═O)CH₂CH₂OCH₃, (C═O)CH═CHCH₂NH(CH₃),                (C═O)CH═CHCH₂N(CH₃)₂, (C═O)CH═CHCH₂OH (C═O)-phenyl,                SO₂CH═CH₂, (C═O)CH₂CH₂SO₂CH₃,

-   -   -   -   -   R^(d) is selected from the group consisting of: H,                    F, OH, and OCH₃;

            -   R^(e) is H or C₁₋₆alkyl;

        -   (c)

-   -   -   where            -   R^(d) is selected from the group consisting of: H, F,                OH, and OCH₃;            -   R^(f) is selected from the group consisting of:                (C═O)—C(R³)═CR⁴(R⁵); H; C₁₋₆alkyl; CN; (C═O)C₁₋₃alkyl;                (C═O)C₁₋₃haloalkyl; (C═O)C₂₋₆alkenyl; (C═O)C₂₋₆alkynyl;                (C═O)(CH₂)₁₋₂OH; (C═O)(CH₂)₁₋₂OCH₃; (C═O)H;                (C═O)(CH₂)₀₋₁CN; (C═O)CH₂NH₂; (C═O)(CH₂)₁₋₂NH(CH₃);                (C═O)(CH₂)₁₋₂N(CH₃)₂; (C═O)CH(CH₃)NH(CH₃);                (C═O)(CH₂)₁₋₂SO₂CH₃; (C═O)CH₂CH(CH₃)(OCH₃);                (C═O)CH(CH₃)CH₂(OH); (C═O)CH(CH₃)CH₂(OCH₃);                (C═O)C(CH₃)₂CH₂(OCH₃); (C═O)CH₂C(CH₃)₂(OCH₃);                (C═O)CH(NH₂)CH₂(OCH₃); (C═O)CH(OCH₃)CH₂(OCH₃);                (C═O)CH(OH)CH₂(OCH₃);

-   -   -   -    C₃₋₆cycloalkyl; (C═O)(CH₂)₀₋₁azetidinyl; (C═O)oxetanyl;                (C═O)tetrahydrofuranyl; (C═O)tetrahydropyranyl;                (C═O)(CH₂)₀₋₁pyrrolidinyl, wherein said pyrrolidinyl is                optionally substituted with CH₃;                (C═O)(CH₂)₀₋₁piperidinyl; (C═O)(CH₂)₀₋₁morpholinyl;                SO₂—C₂₋₆alkenyl; SO₂C₁₋₆alkyl; and linker-PEG-Biotin;                -   R³ is selected from the group consisting of H, CN,                    halogen, C₁₋₆haloalkyl, and C₁₋₆alkyl;                -   R⁴ and R⁵ are each independently selected from the                    group consisting of: H; halogen; C₁₋₆alkyl; CH₂OH;                    C₁₋₆alk-OC₁₋₆alkyl; OC₁₋₆alkyl; C₁₋₄alk-NR⁶R⁷;                    C₃₋₆cycloalkyl substituted with NH₂ or CH₃; oxetanyl                    substituted with CH₃; 1-acetylpyrrolidin-2-yl;                    CH₂-pyrrolidinyl; CH₂-piperidinyl;                    C(CH₃)₂-piperidinyl; CH₂-morpholinyl;                    C(CH₃)₂-morpholinyl;                    CH₂-(4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl;                    C(CH₃)₂NH(CH₂CH₂OCH₃); CH₂SO₂CH₃; CH₂NHSO₂CH₃;                    NH(C═O)C₁₋₆alkyl; and linker-PEG-Biotin; and                -   R⁶ and R⁷ are each independently selected from the                    group consisting of: H, C₁₋₆alkyl, C₃₋₆cycloalkyl,                    and CN;                -   R^(g) is selected from the group consisting of H,                    C₁₋₆alkyl, and CN; and

        -   (d)

where R^(h) is selected from the group consisting of H, CN, CH₃, andCH₂phenyl.

An additional embodiment of the disclosure is directed to compounds ofFormula (III′), as well as the stereoisomers, isotopic variants, andpharmaceutically acceptable salt thereof:

-   -   wherein    -   G-A is selected from the group consisting of:

-   -   where G is phenyl; or phenyl substituted with one or two members        independently selected from the group consisting of: halogen,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₆cycloalkyl, pyridyl, oxetan-3-yl,        and tetrahydro-2H-pyran-4-yl;    -   R^(a) is H or CH₃;    -   Ring B is selected from the group consisting of:

-   -   where R and R^(f) are independently selected from the group        consisting of: H, C₁₋₆alkyl, (C═O)CH═CH₂, (C═O)CH₂NH(CH₃),        (C═O)CH═CHCH₂N(CH₃)₂, and

and R^(d) is selected from the group consisting of: H, OH and OCH₃.

An additional embodiment of the disclosure is directed to compounds ofFormula (IV′), as well as the stereoisomers, isotopic variants, andpharmaceutically acceptable salt thereof:

-   -   wherein    -   G-E-A is selected from the group consisting of:

-   -   -   where G is selected from the group consisting of: C₁₋₆alkyl,            C₃₋₆cycloalkyl, tetrahydro-2H-pyran-4-yl, pyridazin-3-yl,            phenyl, and phenyl substituted with F;        -   R^(a) is H or CH₃;

    -   Ring B is selected from the group consisting of:

-   -   -   R^(c) is selected from the group consisting of: H,            C₁₋₆alkyl, (C═O)C₁₋₃alkyl, (C═O)CH═CH₂, (C═O)C₁₋₆haloalkyl,

and

-   -   R is selected from the group consisting of: H, NH₂, and        NH(C═O)CH═CH₂.

An additional embodiment of the disclosure is directed to compounds ofFormula (V′), as well as the stereoisomers, isotopic variants, andpharmaceutically acceptable salt thereof:

-   -   wherein    -   G is selected from the group consisting of: C₁₋₆alkyl;        C₁₋₆haloalkyl; phenyl; phenyl substituted with one or two        members independently selected from the group consisting of:        halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, OC₁₋₆alkyl, OC₁₋₆haloalkyl,        (C═O)—C₁₋₆alkyl, SF₅, OH, NH₂, N(CH₃)₂, OCH₂CH₂OCH(CH₃)₂, and        SO₂C₁₋₆alkyl; benzo[d][1,3]dioxolyl optionally substituted with        Cl; 2-methylpyridin-3-yl; 2-isopropylpyridin-4-yl;        benzothiophenyl; napthalenyl; and        2,2-difluorobenzo[d][1,3]dioxol-5-yl;    -   Ring B is selected from the group consisting of:

-   -   -   where R^(c) and R^(f) are independently selected from the            group consisting of: H, C₁₋₆alkyl, (C═O)C₁₋₃alkyl,            (C═O)CH═CH₂, (C═O)CH₂NHCH₃,

-   -   -   and

    -   R^(d) is H or OH.

According to the disclosure, R¹ is H or C₁₋₆alkyl. In some aspects, R¹is C₁₋₆alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,s-butyl, or t-butyl. In preferred aspects, R¹ is H.

According to the disclosure R² is a C₀₋₆ alk-heterocycloalkyl moietythat is unsubstituted or substituted with 1, 2, or 3 substituents. Inthose embodiments wherein R² is —C₀ alk-heterocycloalkyl, theheterocycloalkyl is directly attached to the compound of formula Ithrough a bond. In those aspects wherein R² is a —C₁₋₆alk-heterocycloalkyl moiety, the heterocycloalkyl moiety is attached tothe compound of formula I through an aliphatic linker having 1, 2, 3, 4,5, or 6 carbon atoms, wherein the C₁₋₆ alk includes, for example, —CH₂—,—CH(CH₃)—, —CH(CH₃)—CH₂—, and —C(CH₃)₂—. In some embodiments, the C₁₋₆alk linker is substituted by oxo, e.g, —CH₂—C(O)—. In preferred aspects,R² is —C₀₋₁ alk-heterocycloalkyl, for example —C₀alk-heterocycloalkyl(i.e., -heterocycloalkyl) or —C₁ alk-heterocycloalkyl (i.e.,—CH₂-heterocycloalkyl).

In preferred aspects, the R² heterocycloalkyl moiety is a 3-, 4-, 5-, or6-membered heterocycloalkyl, preferably a 5- or 6-memberedheterocycloalkyl, with a 6-membered heterocycloalkyl being mostpreferred. According to the disclosure, the heterocycloalkyl moiety caninclude one nitrogen atom, two nitrogen atoms, one nitrogen atom and oneoxygen atom, or one oxygen atom. Preferred one nitrogen-containingheterocycloalkyl groups for R² are piperidinyl; pyrrolidinyl;azetidinyl; azepanyl; aziridinyl; and quinuclidinyl, with piperidinyland pyrrolidinyl being preferred and piperidinyl being more preferred.Preferred two nitrogen-containing heterocycloalkyl groups for R² areimidazolidinyl and piperazinyl. Preferred one nitrogen, one oxygencontaining heterocycloalkyl groups for R² are oxazepanyl, with1,4-oxazepanyl being preferred; and morpholinyl. Preferred oneoxygen-containing heterocycloalkyl groups for R² are tetrahydropyranyland tetrahydrofuranyl.

In some aspects of the disclosure, R² is —C₀₋₆alk-piperidinyl,preferably —C₀ alk-piperidinyl or —C₁ alk-piperidinyl, optionallysubstituted with 1, 2, or 3 substituents as recited herein. In morepreferred aspects, R² is —C₀₋₆alk-piperidinyl, preferably —C₀alk-piperidinyl or —C₁ alk-piperidinyl, substituted with 1 or 2substituents as recited herein. The substituents can be attached throughany position on the piperidinyl ring. In preferred aspects, at least onesubstituent is attached through the piperidinyl nitrogen atom.

In some aspects of the disclosure, R² is —C₀₋₆alk-pyrrolidinyl,preferably —C₀ alk-pyrrolidinyl or —C₁ alk-pyrrolidinyl, optionallysubstituted with 1, 2, or 3 substituents as recited herein. In morepreferred aspects, R² is —C₀₋₆alk-pyrrolidinyl, preferably —C₀alk-pyrrolidinyl or —C₁ alk-pyrrolidinyl, substituted with 1 or 2substituents as recited herein. The substituents can be attached throughany position on the pyrrolidinyl ring. In preferred aspects, at leastone substituent is attached through the pyrrolidinyl nitrogen atom.

In some aspects of the disclosure, R² is —C₀₋₆alk- oxazepanyl,preferably —C₀ alk-oxazepanyl or —C₁ alk-oxazepanyl, optionallysubstituted with 1, 2, or 3 substituents as recited herein. In morepreferred aspects, R² is —C₀₋₆alk- oxazepanyl, preferably —C₀alk-oxazepanyl or —C₁ alk-oxazepanyl, substituted with 1 or 2substituents as recited herein. The substituents can be attached throughany position on the oxazepanyl ring. In some aspects, at least onesubstituent is attached through the oxazepanyl nitrogen atom.

In some aspects of the disclosure, R² is —C₀₋₆alk-azetidinyl, preferably—C₀ alk-azetidinyl or —C₁ alk-azetidinyl, optionally substituted with 1,2, or 3 substituents as recited herein. In more preferred aspects, R² is—C₀₋₆alk-azetidinyl, preferably —C₀ alk-azetidinyl or —C₁alk-azetidinyl, substituted with 1 or 2 substituents as recited herein.The substituents can be attached through any position on the azetidinylring. In some aspects, at least one substituent is attached through theazetidinyl nitrogen atom.

In some aspects of the disclosure, R² is —C₀₋₆alk-azepanyl, preferably—C₀ alk-azepanyl or —C₁ alk-azepanyl, optionally substituted with 1, 2,or 3 substituents as recited herein. In more preferred aspects, R² is—C₀₋₆alk-azepanyl, preferably —C₀ alk-azepanyl or —C₁ alk-azepanyl,substituted with 1 or 2 substituents as recited herein. The substituentscan be attached through any position on the azepanyl ring. In someaspects, at least one substituent is attached through the azepanylnitrogen atom.

In some aspects of the disclosure, R² is —C₀₋₆alk-aziridinyl, preferably—C₀ alk-aziridinyl or —C₁ alk-aziridinyl, optionally substituted with 1,2, or 3 substituents as recited herein. In more preferred aspects, R² is—C₀₋₆alk-aziridinyl, preferably —C₀ alk-aziridinyl or —C₁alk-aziridinyl, substituted with 1 or 2 substituents as recited herein.The substituents can be attached through any position on the aziridinylring. In some aspects, at least one substituent is attached through theazepanyl nitrogen atom.

In some aspects of the disclosure, R² is —C₀₋₆alk-quinuclidinyl,preferably —C₀ alk-quinuclidinyl or —C₁ alk-quinuclidinyl, optionallysubstituted with 1, 2, or 3 substituents as recited herein. In morepreferred aspects, R² is —C₀₋₆alk-quinuclidinyl, preferably —C₀alk-quinuclidinyl or —C₁ alk-quinuclidinyl, substituted with 1 or 2substituents as recited herein. The substituents can be attached throughany position on the quinuclidinyl ring.

In some aspects of the disclosure, R² is —C₀₋₆alk-imidazolidinyl,preferably —C₀ alk-imidazolidinyl or —C₁ alk-imidazolidinyl, optionallysubstituted with 1, 2, or 3 substituents as recited herein. In morepreferred aspects, R² is —C₀₋₆alk-imidazolidinyl, preferably —C₀alk-imidazolidinyl or —C₁ alk-imidazolidinyl, substituted with 1 or 2substituents as recited herein. The substituents can be attached throughany position on the imidazolidinyl ring. In some aspects, at least onesubstituent is attached through one of the imidazolidinyl nitrogenatoms.

In some aspects of the disclosure, R² is —C₀₋₆alk-piperazinyl,preferably —C₀ alk-piperazinyl or —C₁ alk-piperazinyl, optionallysubstituted with 1, 2, or 3 substituents as recited herein. In morepreferred aspects, R² is —C₀₋₆alk-piperazinyl, preferably —C₀alk-piperazinyl or —C₁ alk-piperazinyl, substituted with 1 or 2substituents as recited herein. The substituents can be attached throughany position on the piperazinyl ring. In some aspects, at least onesubstituent is attached through one of the piperazinyl nitrogen atoms.

In some aspects of the disclosure, R² is —C₀₋₆alk-morpholinyl,preferably —C₀ alk-morpholinyl or —C₁ alk-morpholinyl, optionallysubstituted with 1, 2, or 3 substituents as recited herein. In morepreferred aspects, R² is —C₀₋₆alk-morpholinyl, preferably —C₀alk-morpholinyl or —C₁ alk-morpholinyl, substituted with 1 or 2substituents as recited herein. The substituents can be attached throughany position on the morpholinyl ring. In some aspects, at least onesubstituent is attached the morpholinyl nitrogen atom.

In some aspects of the disclosure, R² is —C₀₋₆alk-tetrahydropyranyl,preferably —C₀ alk-tetrahydropyranyl or —C₁ alk-tetrahydropyranyl,optionally substituted with 1, 2, or 3 substituents as recited herein.In more preferred aspects, R² is —C₀₋₆alk-tetrahydropyranyl, preferably—C₀ alk-tetrahydropyranyl or —C₁ alk-tetrahydropyranyl, substituted with1 or 2 substituents as recited herein. The substituents can be attachedthrough any carbon atom on the tetrahydropyranyl ring.

In some aspects of the disclosure, R² is —C₀₋₆alk-tetrahydrofuranyl,preferably —C₀ alk-tetrahydrofuranyl or —C₁ alk-tetrahydrofuranyl,optionally substituted with 1, 2, or 3 substituents as recited herein.In more preferred aspects, R² is —C₀₋₆alk-tetrahydrofuranyl, preferably—C₀ alk-tetrahydrofuranyl or —C₁ alk-tetrahydrofuranyl, substituted with1 or 2 substituents as recited herein. The substituents can be attachedthrough any carbon atom on the tetrahydrofuranyl ring.

In preferred aspects of the disclosure, R² is piperidinyl,CH₂CH₂-piperidinyl, pyrrolidinyl, CH₂-pyrrolidinyl, orCH₂CH₂-pyrrolidinyl. In other preferred aspects, R² is azetidinyl;azepanyl; quinuclidinyl; CH₂CH₂-imidazolidinyl; or CH₂CH₂-piperazinyl.In some aspects, R² is oxazepanyl or CH₂CH₂-morpholinyl,CH₂(C═O)-morpholinyl. In other aspects, R² is tetrahydropyranyl ortetrahydrofuranyl, or CH₂-tetrahydrofuranyl.

In some aspects, the R² moiety can be defined as “Ring B.” In someaspects, particularly those wherein the compound is of Formula (II′),Ring B is

wherein R^(b) is selected from the group consisting of: H; C₁₋₆alkyl,C₃₋₆cycloalkyl, (C═O)CH═CH₂, (C═O)CH₂CH₂OCH₃, (C═O)CH₂CH₂SO₂CH₃, and

In other aspects, Ring B is selected from the group consisting of:

wherein R^(c) is selected from the group consisting of: H, C₁₋₆alkyl,CN, (C═O)C₁₋₃alkyl, (C═O)CH═CH₂, C₃₋₆cycloalkyl, (C═O)CH₂NH₂,(C═O)CH₂NH(CH₃), (C═O)CH₂N(CH₃)₂, (C═O)CH₂CN, CH₂-phenyl, (C═O)CH₂Cl,(C═O)CH═CHCH₂NH₂, (C═O)CH₂CH₂OCH₃, (C═O)CH═CHCH₂NH(CH₃),(C═O)CH═CHCH₂N(CH₃)₂, (C═O)CH═CHCH₂OH, (C═O)-phenyl, SO₂CH═CH₂,(C═O)CH₂CH₂SO₂CH₃,

R^(d) is selected from the group consisting of: H, F, OH, and OCH₃; andR^(e) is H or C₁₋₆alkyl. In other aspects, Ring B is selected from thegroup consisting of

wherein R^(d) is selected from the group consisting of: H, F, OH, andOCH₃; R^(f) is selected from the group consisting of:(C═O)—C(R³)═CR⁴(R⁵); H; C₁₋₆alkyl; CN; (C═O)C₁₋₃alkyl;(C═O)C₁₋₃haloalkyl; (C═O)C₂₋₆alkenyl; (C═O)C₂₋₆alkynyl; (C═O)(CH₂)₁₋₂OH;(C═O)(CH₂)₁₋₂OCH₃; (C═O)H; (C═O)(CH₂)₀₋₁CN; (C═O)CH₂NH₂;(C═O)(CH₂)₁₋₂NH(CH₃); (C═O)(CH₂)₁₋₂N(CH₃)₂; (C═O)CH(CH₃)NH(CH₃);(C═O)(CH₂)₁₋₂SO₂CH₃; (C═O)CH₂CH(CH₃)(OCH₃); (C═O)CH(CH₃)CH₂(OH);(C═O)CH(CH₃)CH₂(OCH₃); (C═O)C(CH₃)₂CH₂(OCH₃); (C═O)CH₂C(CH₃)₂(OCH₃);(C═O)CH(NH₂)CH₂(OCH₃); (C═O)CH(OCH₃)CH₂(OCH₃); (C═O)CH(OH)CH₂(OCH₃);

C₃₋₆cycloalkyl; (C═O)(CH₂)₀₋₁azetidinyl; (C═O)oxetanyl;(C═O)tetrahydrofuranyl; (C═O)tetrahydropyranyl;(C═O)(CH₂)₀₋₁pyrrolidinyl, wherein said pyrrolidinyl is optionallysubstituted with CH₃; (C═O)(CH₂)₀₋₁piperidinyl;(C═O)(CH₂)₀₋₁morpholinyl; SO₂—C₂₋₆alkenyl; SO₂C₁₋₆alkyl; andlinker-PEG-Biotin; wherein R³ is selected from the group consisting of:H, CN, halogen, C₁₋₆haloalkyl, and C₁₋₆alkyl; R⁴ and R⁵ are eachindependently selected from the group consisting of: H; halogen;C₁₋₆alkyl; CH₂OH; C₁₋₆alk-OC₁₋₆alkyl; OC₁₋₆alkyl; C₁₋₄alk-NR⁶R⁷;C₃₋₆cycloalkyl substituted with NH₂ or CH₃; oxetanyl substituted withCH₃; 1-acetylpyrrolidin-2-yl; CH₂-pyrrolidinyl; CH₂-piperidinyl;C(CH₃)₂-piperidinyl; CH₂-morpholinyl; C(CH₃)₂-morpholinyl;CH₂-(4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl;C(CH₃)₂NH(CH₂CH₂OCH₃); CH₂SO₂CH₃; CH₂NHSO₂CH₃; NH(C═O)C₁₋₆alkyl; andlinker-PEG-Biotin; andR⁶ and R⁷ are each independently selected from the group consisting of:H, C₁₋₆alkyl, C₃₋₆cycloalkyl, and CN; and R^(g) is selected from thegroup consisting of: H, C₁₋₆alkyl, and CN. In other aspects, Ring B isselected from the group consisting of

wherein R^(h) is selected from the group consisting of: H, CN, CH₃, andCH₂phenyl. In preferred aspects, Ring B is selected from the groupconsisting of

and R^(c) and R^(f) are (C═O)CH═CH₂; and R^(d) is H.

In some aspects, the R² moiety can be defined as “Ring B.” In someaspects, particularly those wherein the compound is of Formula (III′),Ring B is selected from the group consisting of

wherein R^(c) and R^(f) are independently selected from the groupconsisting of: H, C₁₋₆alkyl, (C═O)CH═CH₂, (C═O)CH₂NH(CH₃),(C═O)CH═CHCH₂N(CH₃)₂, and

and R^(d) is selected from the group consisting of: H, OH and OCH₃. Inpreferred aspects, Ring B is selected from the group consisting of

and R^(c) and R^(f) are (C═O)CH═CH₂; and R^(d) is H.

In some aspects, the R² moiety can be defined as “Ring B.” In someaspects, particularly those wherein the compound is of Formula (IV′),Ring B is selected from the group consisting of

wherein R^(c) is selected from the group consisting of: H, C₁₋₆alkyl,(C═O)C₁₋₃alkyl, (C═O)CH═CH₂, (C═O)C₁₋₆haloalkyl,

and R^(j) is selected from the group consisting of: H, NH₂, andNH(C═O)CH═CH₂. In preferred aspects, Ring B is selected from the groupconsisting of

and R^(c) and R^(f) are (C═O)CH═CH₂.

In some aspects, the R² moiety can be defined as “Ring B.” In someaspects, particularly those wherein the compound is of Formula (V′),Ring B is selected from the group consisting of

where R^(c) and R^(f) are independently selected from the groupconsisting of: H, C₁₋₆alkyl, (C═O)C₁₋₃alkyl, (C═O)CH═CH₂, (C═O)CH₂NHCH₃,

and R^(d) is H or OH.

According to the disclosure, in some embodiments, the R²heterocycloalkyl is unsubstituted. In preferred aspects, the R²heterocycloalkyl is substituted with 1, 2, or 3 substituents. Inpreferred aspects, the R² heterocycloalkyl is substituted with 1 or 2substituents, more preferably 1 substituent. In those aspects whereinthe R² heterocycloalkyl is substituted, the substituents may beindependently selected from the group consisting of—NR—C(O)—C(R³)═CR⁴(R⁵); —C(O)—C(R³)═CR⁴(R⁵); oxo; halogen; —CN; —OH;—NR⁶R⁷; —C₁₋₆alkyl; —C₁₋₆alk-OH; —OC₁₋₆alkyl; —C₃₋₆cycloalkyl;—C₁₋₆haloalkyl; —C₁₋₆alkaryl; —SO₂C₁₋₆alkyl; —SO₂C₂₋₆alkenyl; —C(O)H;—C(O)—C₁₋₆alkyl; —C(O)—C₃₋₆cycloalkyl; —C(O)—C₁₋₆haloalkyl;—C(O)—C₂₋₆alkynyl; —C(O)—C₆₋₁₀aryl; —C(O)-heteroaryl; —C(O)—C₁₋₆alk-CN;—C(O)—C₁₋₆alk-OH; —C(O)—C₁₋₆alk-SO₂—C₁₋₆alkyl; —C(O)—O—C₁₋₆alkyl;—C(O)—C₁₋₆alk-NR⁶R⁷; —C(O)—C₁₋₆alk-O—C₁₋₆alkyl wherein the -alk- isoptionally substituted with —OH, —OC₁₋₆alkyl, or —NR⁶R⁷; and—C(O)—C₀₋₆alk-heterocycloalkyl wherein the -alk- is optionallysubstituted with oxo and the heterocycloalkyl is optionally substitutedwith —C₁₋₆alkyl; and wherein R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as definedherein. In those aspects wherein the R² heterocycloalkyl is substituted,the substituents are preferably independently selected from the groupconsisting of —NR⁸—C(O)—C(R³)═CR⁴(R⁵); —C(O)—C(R³)═CR⁴(R⁵); oxo;halogen; —CN; —OH; —NR⁶R⁷; —C₁₋₆alk-OH; —OC₁₋₆alkyl; —C₃₋₆cycloalkyl;—C₁₋₆haloalkyl; —C₁₋₆alkaryl; —SO₂C₁₋₆alkyl; —SO₂C₂₋₆alkenyl; —C(O)H;—C(O)—C₁₋₆alkyl; —C(O)—C₃₋₆cycloalkyl; —C(O)—C₁₋₆haloalkyl;—C(O)—C₂₋₆alkynyl; —C(O)—C₆₋₁₀aryl; —C(O)-heteroaryl; —C(O)—C₁₋₆alk-CN;—C(O)—C₁₋₆alk-OH; —C(O)—C₁₋₆alk-SO₂—C₁₋₆alkyl; —C(O)—C₁₋₆alk-NR⁶R⁷;—C(O)—C₁₋₆alk-O—C₁₋₆alkyl wherein the -alkis optionally substituted with—OH, —OC₁₋₆alkyl, or —NR⁶R⁷; and —C(O)—C₀₋₆alk-heterocycloalkyl whereinthe -alk- is optionally substituted with oxo and the heterocycloalkyl isoptionally substituted with —C₁₋₆alkyl; and wherein R³, R⁴, R⁵, R⁶, R⁷,and R⁸ are as defined herein.

In some aspects, the R² heterocycloalkyl is substituted with an oxomoiety, for example one oxo moiety. In those aspects wherein the R²heterocycloalkyl is substituted with an oxo moiety, the heterocycloalkylring may optionally be substituted with one or two additionalsubstituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with a halogen,for example a fluorine or chlorine. In some aspects, the R²heterocycloalkyl is substituted with one or two halogens, preferably onehalogen. In those aspects wherein the R² heterocycloalkyl is substitutedwith a halogen, the heterocycloalkyl ring may optionally be substitutedwith one or two additional substituents as defined herein for the R²substituents.

In some aspects, the R² heterocycloalkyl is substituted with —CN. Insome aspects, the R² heterocycloalkyl is substituted with one or two—CN, preferably one —CN. In those aspects wherein the R²heterocycloalkyl is substituted with —CN, the heterocycloalkyl ring mayoptionally be substituted with one or two additional substituents asdefined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with —OH. Insome aspects, the R² heterocycloalkyl is substituted with one or two—OH, preferably one —OH. In those aspects wherein the R²heterocycloalkyl is substituted with —OH, the heterocycloalkyl ring mayoptionally be substituted with one or two additional substituents asdefined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with —NR⁶R⁷wherein R⁶ and R⁷ are each independently H; —C₁₋₆alkyl, —C₃₋₆cycloalkyl;—C(O)H; or —CN. In preferred aspects, R⁶ and R⁷ are each independently Hor —C₁₋₆alkyl. In those aspects wherein the R² heterocycloalkyl issubstituted with —NR⁶R⁷, the heterocycloalkyl ring may optionally besubstituted with one or two additional substituents as defined hereinfor the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or—C₁alkyl. In some aspects, the R² heterocycloalkyl is substituted withone or two —C₁₋₆alkyl, preferably one —C₁₋₆alkyl. In those aspectswherein the R² heterocycloalkyl is substituted with —C₁₋₆alkyl, theheterocycloalkyl ring may optionally be substituted with one or twoadditional substituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C₁₋₆alk-OH, for example, —C₁₋₅alk-OH, —C₁₋₄alk-OH, —C₁₋₃alk-OH,—C₁₋₂alk-OH, or —C₁alk-OH, wherein the —OH moiety can be attached to anycarbon of the —C₁₋₆alk group, preferably the co carbon. In some aspects,the R² heterocycloalkyl is substituted with one or two —C₁₋₆alk-OH,preferably one —C₁₋₆alk-OH. In those aspects wherein the R²heterocycloalkyl is substituted with —C₁₋₆alk-OH, the heterocycloalkylring may optionally be substituted with one or two additionalsubstituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—OC₁₋₆alkyl, for example, —O—C₁₋₅alkyl, —O—C₁₋₄alkyl, —O—C₁₋₃alkyl,—O—C₁₋₂alkyl, or —O-C₁alkyl. In some aspects, the R² heterocycloalkyl issubstituted with one or two —OC₁₋₆alkyl, preferably one —OC₁₋₆alkyl. Inthose aspects wherein the R² heterocycloalkyl is substituted with—OC₁₋₆alkyl, the heterocycloalkyl ring may optionally be substitutedwith one or two additional substituents as defined herein for the R²substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C₃₋₆cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In some aspects, the R² heterocycloalkyl is substituted withone or two —C₃₋₆cycloalkyl, preferably one —C₃₋₆cycloalkyl. In thoseaspects wherein the R² heterocycloalkyl is substituted with—C₃₋₆cycloalkyl, the heterocycloalkyl ring may optionally be substitutedwith one or two additional substituents as defined herein for the R²substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C₁₋₆haloalkyl, for example, —C₁-haloalkyl, —C₁₋₄haloalkyl,—C₁₋₃haloalkyl, —C₁₋₂haloalkyl, or —C₁haloalkyl, including —CF₃,—CH₂CH₂F, and the like. In some aspects, the R² heterocycloalkyl issubstituted with one or two —C₁₋₆haloalkyl, preferably one—C₁₋₆haloalkyl. In those aspects wherein the R² heterocycloalkyl issubstituted with —C₁₋₆haloalkyl, the heterocycloalkyl ring mayoptionally be substituted with one or two additional substituents asdefined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C₁₋₆alkaryl, for example, benzyl (i.e., —CH₂-phenyl). In some aspects,the R² heterocycloalkyl is substituted with one or two —C₁₋₆alkaryl,preferably one —C₁₋₆alkaryl. In those aspects wherein the R²heterocycloalkyl is substituted with —C₁₋₆alkaryl, the heterocycloalkylring may optionally be substituted with one or two additionalsubstituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—SO₂C₁₋₆alkyl, for example, —SO₂—C₁₋₅alkyl, —SO₂—C₁₋₄alkyl,—SO₂—C₁₋₃alkyl, —SO₂—C₁₋₂alkyl, or —SO₂—C₁alkyl. In some aspects, the R²heterocycloalkyl is substituted with one or two —SO₂C₁₋₆alkyl,preferably one —SO₂C₁₋₆alkyl. In those aspects wherein the R²heterocycloalkyl is substituted with —SO₂C₁₋₆alkyl, the heterocycloalkylring may optionally be substituted with one or two additionalsubstituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—SO₂C₂₋₆alkenyl, for example, —SO₂C₂₋₅alkenyl, —SO₂C₂₋₄alkenyl,—SO₂C₂₋₃alkenyl, or —SO₂C₂alkenyl. In some aspects, the R²heterocycloalkyl is substituted with one or two —SO₂C₂₋₆alkenyl,preferably one —SO₂C₂₋₆alkenyl. In those aspects wherein the R²heterocycloalkyl is substituted with —SO₂C₂₋₆alkenyl, theheterocycloalkyl ring may optionally be substituted with one or twoadditional substituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with —C(O)H. Insome aspects, the R² heterocycloalkyl is substituted with one or two—C(O)H, preferably one —C(O)H. In those aspects wherein the R²heterocycloalkyl is substituted with —C(O)H, the heterocycloalkyl ringmay optionally be substituted with one or two additional substituents asdefined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C(O)—C₁₋₆alkyl, for example, —C(O)—C₁₋₅alkyl, —C(O)—C₁₋₄alkyl,—C(O)—C₁₋₃alkyl, —C(O)—C₁₋₂alkyl, or —C(O)— C₁alkyl. In some aspects,the R² heterocycloalkyl is substituted with one or two —C(O)—C₁₋₆alkyl,preferably one —C(O)—C₁₋₆alkyl. In those aspects wherein the R²heterocycloalkyl is substituted with —C(O)—C₁₋₆alkyl, theheterocycloalkyl ring may optionally be substituted with one or twoadditional substituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C(O)—C₃₋₆cycloalkyl, for example, —C(O)-cyclopropyl, —C(O)-cyclobutyl,—C(O)-cyclopentyl, or —C(O)-cyclohexyl. In some aspects, the R²heterocycloalkyl is substituted with one or two —C(O)—C₃₋₆cycloalkyl,preferably one —C(O)—C₃₋₆cycloalkyl. In those aspects wherein the R²heterocycloalkyl is substituted with —C(O)—C₃₋₆cycloalkyl, theheterocycloalkyl ring may optionally be substituted with one or twoadditional substituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C(O)—C₁₋₆haloalkyl, for example, —C(O)—C₁₋₆haloalkyl,—C(O)—C₁₋₄haloalkyl, —C(O)—C₁₋₃haloalkyl, —C(O)—C₁₋₂haloalkyl, or—C(O)—C₁haloalkyl, including —C(O)—CF₃, —C(O)—CH₂CH₂F, and the like. Insome aspects, the R² heterocycloalkyl is substituted with one or two—C(O)—C₁₋₆haloalkyl, preferably one —C(O)—C₁₋₆haloalkyl. In thoseaspects wherein the R² heterocycloalkyl is substituted with—C(O)—C₁₋₆haloalkyl, the heterocycloalkyl ring may optionally besubstituted with one or two additional substituents as defined hereinfor the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C(O)—C₂₋₆alkynyl, for example, —C(O)—C₂₋₅alkynyl, —C(O)—C₂₋₄alkynyl,—C(O)—C₂₋₃alkynyl, or —C(O)—C₂alkynyl. In some aspects, the R²heterocycloalkyl is substituted with one or two —C(O)—C₂₋₆alkynyl,preferably one —C(O)—C₂₋₆alkynyl. In those aspects wherein the R²heterocycloalkyl is substituted with —C(O)—C₂₋₆alkynyl, theheterocycloalkyl ring may optionally be substituted with one or twoadditional substituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C(O)—C₆₋₁₀aryl, for example, —C(O)-phenyl or —C(O)-napthalenyl. In someaspects, the R² heterocycloalkyl is substituted with one or two—C(O)—C₆₋₁₀aryl, preferably one —C(O)—C₆₋₁₀aryl. In those aspectswherein the R² heterocycloalkyl is substituted with —C(O)—C₆₋₁₀aryl, theheterocycloalkyl ring may optionally be substituted with one or twoadditional substituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C(O)-heteroaryl, for example, —C(O)-pyrrolyl, —C(O)-thienyl,—C(O)-oxazolyl, —C(O)-pyrazolyl, —C(O)-pyridyl, —C(O)-pyrimidinyl, andthe like. In some aspects, the R² heterocycloalkyl is substituted withone or two —C(O)-heteroaryl, preferably one —C(O)-heteroaryl. In thoseaspects wherein the R² heterocycloalkyl is substituted with—C(O)-heteroaryl, the heterocycloalkyl ring may optionally besubstituted with one or two additional substituents as defined hereinfor the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C(O)—C₁₋₆alk-CN, for example, —C(O)—C₁₋₅alk-CN, —C(O)—C₁₋₄alk-CN,—C(O)—C₁₋₃alk-CN, —C(O)—C₁₋₂alk-CN, or —C(O)—C₁alk-CN. In some aspects,the R² heterocycloalkyl is substituted with one or two —C(O)—C₁₋₆alk-CN,preferably one —(C(O)—C₁₋₆alk-CN. In those aspects wherein the R²heterocycloalkyl is substituted with —C(O)—C₁₋₆alk-CN, theheterocycloalkyl ring may optionally be substituted with one or twoadditional substituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C(O)—C₁₋₆alk-OH, for example, —C(O)—C₁₋₅alk-OH, —C(O)—C₁₋₄alk-OH,—C(O)—C₁₋₃alk-OH, —C(O)—C₁₋₂alk-OH, or —C(O)—C₁alk-OH. In some aspects,the R² heterocycloalkyl is substituted with one or two —C(O)—C₁₋₆alk-OH,preferably one —C(O)—C₁₋₆alk-OH. The —OH moiety can be attached to anycarbon of the —C₁₋₆alk group, preferably the ω carbon. In those aspectswherein the R² heterocycloalkyl is substituted with —C(O)—C₁₋₆alk-OH,the heterocycloalkyl ring may optionally be substituted with one or twoadditional substituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C(O)—C₁₋₆alk-SO₂—C₁₋₆alkyl, for example, —C(O)—C₁₋₅alk-SO₂—C₁₋₅alkyl,—C(O)—C₁₋₄alk-SO₂—C₁₋₄alkyl, —C(O)—C₁₋₃alk-SO₂—C₁₋₃alkyl,—C(O)—C₁₋₂alk-SO₂—C₁₋₂alkyl, or —C(O)—C₁alk-SO₂—C₁alkyl. In someaspects, the R² heterocycloalkyl is substituted with one or two—C(O)—C₁₋₆alk-SO₂—C₁₋₆alkyl, preferably one —C(O)—C₁₋₆alk-SO₂—C₁₋₆alkyl.In those aspects wherein the R² heterocycloalkyl is substituted with—C(O)—C₁₋₆alk-SO₂—C₁₋₆alkyl, the heterocycloalkyl ring may optionally besubstituted with one or two additional substituents as defined hereinfor the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C(O)—O—C₁₋₆alkyl, for example, —C(O)—O—C₁₋₅alkyl, —C(O)—O—C₁₋₄alkyl,—C(O)—O—C₁₋₃alkyl, —C(O)—O—C₁₋₂alkyl, or —C(O)—O-C₁alkyl. In someaspects, the R² heterocycloalkyl is substituted with one or two—C(O)—O—C₁₋₆alkyl, preferably one —C(O)—O—C₁₋₆alkyl. In those aspectswherein the R² heterocycloalkyl is substituted with —C(O)—O—C₁₋₆alkyl,the heterocycloalkyl ring may optionally be substituted with one or twoadditional substituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C(O)—C₁₋₆alk-NR⁶R⁷, for example,—C(O)—C₁₋₅alk-NR⁶R⁷′—C(O)—C₁₋₄alk-NR⁶R⁷′—C(O)—C₁₋₃alk-NR⁶R⁷′—C(O)—C₁₋₂alk-NR⁶R⁷, or —C(O)—C₁alk-NR⁶R⁷, wherein R⁶ and R⁷ are eachindependently H; —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl; —C₃₋₆cycloalkyl, for example,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; —C(O)H, or —CN. Inpreferred aspects, R⁶ and R⁷ are each independently H, —C₁₋₆alkyl; or—C₃₋₆cycloalkyl, with H and —C₁₋₆alkyl being preferred, and H and—C₁₋₂alkyl being more preferred. In some aspects, the R²heterocycloalkyl is substituted with one or two —C(O)—C₁₋₆alk-NR⁶R⁷,preferably one —C(O)—C₁₋₆alk-NR⁶R⁷. In those aspects wherein the R²heterocycloalkyl is substituted with —C(O)—C₁₋₆alk-NR⁶R⁷, theheterocycloalkyl ring may optionally be substituted with one or twoadditional substituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C(O)—C₁₋₆alk-O—C₁₋₆alkyl, for example, —C(O)—C₁₋₅alk-O—C₁₋₅alkyl,—C(O)—C₁₋₄alk-O—C₁₋₄alkyl, —C(O)—C₁₋₃alk-O—C₁₋₃alkyl,—C(O)—C₁₋₂alk-O—C₁₋₂alkyl, or —C(O)—C₁alk-O-C₁alkyl. In certain aspectswherein the R² heterocycloalkyl is substituted with—C(O)—C₁₋₆alk-O—C₁₋₆alkyl, the —C₁₋₆alk- is optionally substituted with—OH; —OC₁₋₆alkyl, for example, —OC₁₋₅alkyl, —OC₁₋₄alkyl, —OC₁₋₃alkyl,—OC₁₋₂alkyl, or —OC₁alkyl; or —NR⁶R⁷ (wherein R⁶ and R⁷ are eachindependently H; —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl; —C₃₋₆cycloalkyl; —C(O)H; or —CN).In preferred aspects, R⁶ and R⁷ are each independently H, —C₁₋₆alkyl; or—C₃₋₆cycloalkyl, with H and —C₁₋₆alkyl being preferred, and H and—C₁₋₂alkyl being more preferred. In some aspects, the —C₁₋₆alk- of the—C(O)—C₁₋₆alk-O—C₁₋₆alkyl moiety is substituted with —OH. In otheraspects, the —C₁₋₆alk- is substituted with —OC₁₋₆alkyl, for example,—OC₁₋₅alkyl, —OC₁₋₄alkyl, —OC₁₋₃alkyl, —OC₁₋₂alkyl, or —OC₁alkyl. Insome aspects, the R² heterocycloalkyl is substituted with one or two—C(O)—C₁₋₆alk-O—C₁₋₆alkyl, preferably one —C(O)—C₁₋₆alk-O—C₁₋₆alkyl. Inthose aspects wherein the R² heterocycloalkyl is substituted with—C(O)—C₁₋₆alk-O—C₁₋₆alkyl, the heterocycloalkyl ring may optionally besubstituted with one or two additional substituents as defined hereinfor the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—C(O)—C₀₋₆alk-heterocycloalkyl, for example,—C(O)—C₀₋₅alk-heterocycloalkyl, —C(O)—C₀₋₄alk-heterocycloalkyl,—C(O)—C₀₋₃alk-heterocycloalkyl, —C(O)—C₀₋₂alk-heterocycloalkyl,—C(O)—C₀₋₁alk-heterocycloalkyl, —C(O)—C₁alk-heterocycloalkyl, or—C(O)—C₀alk-heterocycloalkyl. Preferred substituent heterocycloalkylgroups include tetrahydrofuranyl, piperidinyl, pyrrolidinyl, and thelike. In certain aspects wherein the R² heterocycloalkyl is substitutedwith —C(O)—C₁₋₆alk-heterocycloalkyl, the —C₁₋₆alk- is optionallysubstituted with oxo. In certain aspects wherein the R² heterocycloalkylis substituted with —C(O)—C₀₋₆alk-heterocycloalkyl, the substituentheterocycloalkyl moiety can be unsubstituted or substituted with—C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl,or —C₁alkyl. In those aspects wherein the R² heterocycloalkyl issubstituted with —C(O)—C₀₋₆alk-heterocycloalkyl, the R² heterocycloalkylring may optionally be substituted with one or two additionalsubstituents as defined herein for the R² substituents.

In some aspects, the R² heterocycloalkyl is substituted with—NR⁸—C(O)—C(R³)═CR⁴(R⁵), wherein R³, R⁴, and R⁵ are as described hereinand R⁸ is H or C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl. In preferred aspects, R⁸ is H. Inthese aspects, R³ is H; —CN; halogen; —C₁₋₆haloalkyl; or —C₁₋₆alkyl. Insome embodiments, R³ is H. In other aspects, R³ is —CN. In still otheraspects, R³ is halogen, for example F or Cl. In yet other aspects, R³ is—C₁₋₆haloalkyl, for example, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl,—C₁₋₃haloalkyl, —C₁₋₂haloalkyl, or —C₁haloalkyl, including —CF₃,—CH₂CH₂F, and the like. In further aspects, R³ is —C₁₋₆alkyl, forexample, —C₁-alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or -C₁alkyl. Inthose aspects wherein the R² heterocycloalkyl is substituted with—NR⁸—C(O)—C(R³)═CR⁴(R⁵), the heterocycloalkyl ring may optionally besubstituted with one or two additional substituents as defined hereinfor the R² substituents.

In preferred aspects of the disclosure, the R² heterocycloalkyl issubstituted with —C(O)—C(R³)═CR⁴(R⁵). In these embodiments, R³ is H;—CN; halogen; —C₁₋₆haloalkyl; or —C₁₋₆alkyl. In some embodiments, R³ isH. In other aspects, R³ is —CN. In still other aspects, R³ is halogen,for example F or Cl. In yet other aspects, R³ is —C₁₋₆haloalkyl, forexample, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl, —C₁₋₃haloalkyl, —C₁₋₂haloalkyl,or —C₁haloalkyl, including —CF₃, —CH₂CH₂F, and the like. In furtheraspects, R³ is —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl. In those aspects wherein the R²heterocycloalkyl is substituted with —C(O)—C(R³)═CR⁴(R⁵), theheterocycloalkyl ring may optionally be substituted with one or twoadditional substituents as defined herein for the R² substituents.

In preferred aspects, the R² heterocycloalkyl is substituted with—C(O)—C(R³)═CR⁴(R⁵); —C(O)—C₁₋₆alk-NR⁶R⁷; —C(O)—C₁₋₆alkyl; or —NR⁶R⁷. Inmore preferred aspects, the R² heterocycloalkyl is substituted with—C(O)—C(R³)═CR⁴(R⁵). In other preferred aspects, the R² heterocycloalkylis substituted with —C(O)—C₁₋₆alk-NR⁶R⁷; —C(O)—C₁₋₆alkyl; or —NR⁶R⁷;wherein R⁶ and R⁷ are each independently H or C₁₋₆alkyl.

In other aspects, the R² is substituted with halogen; CN; OH; C₁₋₆alkyl;C₁₋₆haloalkyl; C₁₋₆alk-OH; OC₁₋₆alkyl; C₃₋₆cycloalkyl; NH₂; orC₁₋₂alkaryl. In yet other aspects, the R² is substituted with C═O)H;(C═O)C₁₋₆alkyl; (C═O)C₃₋₆cycloalkyl; (C═O)C₁₋₆haloalkyl; (C═O)-alkynyl;(C═O)-phenyl; (C═O)—C₁₋₆alkCN; (C═O)—C₁₋₆alk-OH; (C═O)—C₁₋₆alk-NR⁶R⁷; or(C═O)—C₁₋₆alk-O—C₁₋₆alkyl wherein the —C₁₋₆alk- is optionallysubstituted with OH, OC₁₋₆alkyl, or NR⁶R⁷. In some aspects, the R² issubstituted with (C═O)C₀₋₁alk-heterocycloalkyl wherein theheterocycloalkyl is optionally substituted with C₁₋₆alkyl. In otheraspects, the R² is substituted with SO₂alkyl,(C═O)—C₁₋₆alk-SO₂C₁₋₆alkyl, or SO₂—C₂₋₆alkenyl.

In those embodiments employing R⁴ and R⁵, that is, those aspects whereinthe R² heterocycloalkyl is substituted with —C(O)—C(R³)═CR⁴(R⁵) or—NR⁸—C(O)—C(R³)═CR⁴(R⁵), R⁴ and R⁵ are each independently H; halogen;—C₁₋₆alkyl; —OC₁₋₆alkyl; —C₀₋₆alk-C₃₋₆cycloalkyl optionally substitutedwith —C₁₋₆alkyl; —C₁₋₆alk-OH; —C₀₋₆alk-NR⁶R⁷; —C₁₋₆alk-O—C₁₋₆alkyl;—C₁₋₆alk-NH—C₀₋₆alk-O—C₁₋₆alkyl; —C₀₋₆alk-heterocycloalkyl optionallysubstituted with —C(O)C₁₋₆alkyl or —C₁₋₆alkyl; —C₁₋₆alk-NHSO₂—C₁₋₆alkyl;—C₁₋₆alk-SO₂—C₁₋₆alkyl; —NHC(O)—C₁₋₆alkyl; or linker-PEG-Biotin.

Within the scope of the disclosure, the double bond present in either—C(O)—C(R³)═CR⁴(R⁵) or —NR⁸—C(O)—C(R³)═CR⁴(R⁵) may be of the Z or Econfiguration.

In some aspects, neither R⁴ nor R⁵ is H.

In most preferred aspects, each of R⁴ and R⁵ is H.

In some aspects, one of R⁴ and R⁵ is H. In certain of these aspects, theother of R⁴ and R⁵ is halogen, for example F or Cl.

In some aspects, one of R⁴ and R⁵ is H. In certain of these aspects, theother of R⁴ and R⁵ is —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl.

In some aspects, one of R⁴ and R⁵ is H. In certain of these aspects, theother of R⁴ and R⁵ is —OC₁₋₆alkyl, for example, —OC₁₋₅alkyl,—OC₁₋₄alkyl, —OC₁₋₃alkyl, —OC₁₋₂alkyl, or —OC₁alkyl.

In some aspects, one of R⁴ and R⁵ is H. In certain of these aspects, theother of R⁴ and R⁵ is —C₀₋₆alk-C₃₋₆cycloalkyl, for example,—C₀₋₅alk-C₃₋₅cycloalkyl, —C₀₋₄alk-C₃₋₄cycloalkyl, —C₀₋₃alk-C₃cycloalkyl,—C₀₋₂alk-C₃₋₆cycloalkyl, —C₀₋₁alk-C₃₋₆cycloalkyl,—C₀alk-C₃₋₆cycloalkylor -C₁alk-C₃₋₆cycloalkyl. In these aspects, the cycloalkyl moiety can beunsubstituted or can be substituted with —C₁₋₆alkyl, for example,—C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl. Thesubstitution can be a spiro-substitution or a non-spiro-substitution.

In some aspects, one of R⁴ and R⁵ is H. In certain of these aspects, theother of R⁴ and R⁵ is —C₀₋₆alk-heterocycloalkyl, for example,—C₁₋₆alk-heterocycloalkyl, —C₀₋₄alk-heterocycloalkyl,—C₀₋₃alk-heterocycloalkyl, —C₀₋₂alk-heterocycloalkyl,—C₀₋₁alk-heterocycloalkyl,—C₁alk-heterocycloalkyl, or—C₀alk-heterocycloalkyl. In these aspects, the substituentheterocycloalkyl is preferably an oxygen-containing heterocycloalkyl,for example, tetrahydropyranyl, tetrahydrofuranyl, or oxetanyl. In otheraspects, the heterocycloalkyl is a nitrogen-containing heterocycloalkyl,for example, pyrrolidinyl, aziridinyl, or piperidinyl. In certain ofthese aspects, the substituent heterocycloalkyl can be substituted with—C(O)C₁₋₆alkyl, for example, —C(O)C₁₋₅alkyl, —C(O)C₁₋₄alkyl,—C(O)C₁₋₃alkyl, —C(O)C₁₋₂alkyl, or —C(O)C₁alkyl. In other aspects, thesubstituent heterocycloalkyl can be substituted with —C₁₋₆alkyl, forexample, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl.

In some aspects, one of R⁴ and R⁵ is H. In certain of these aspects, theother of R⁴ and R⁵ is —C₁₋₆alk-OH, for example, —C₁₋₅alk-OH,—C₁₋₄alk-OH, —C₁₋₃alk-OH, —C₁₋₂alk-OH, or -C₁alk-OH. The —OH moiety canbe attached to any carbon of the —C₁₋₆alk group, preferably the ωcarbon.

In some aspects, one of R⁴ and R⁵ is H. In certain of these aspects, theother of R⁴ and R⁵ is —C₀₋₆alk-NR⁶R⁷, for example, —C₀₋₅alk-NR⁶R⁷,—C₀₋₄alk-NR⁶R⁷, —C₀₋₃alk-NR⁶R⁷, —C₀₋₂alk-NR⁶R⁷, —C₀₋₁alk-NR⁶R⁷,C₁alk-NR⁶R⁷, or —C₀alk-NR⁶R⁷, wherein R⁶ and R⁷ are each independentlyH; —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl,—C₁₋₂alkyl, or -C₁alkyl; —C₃₋₆cycloalkyl, for example, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl; —C(O)H; or —CN. In preferredaspects, R⁶ and R⁷ are each independently H; —C₁₋₆alkyl; or—C₃₋₆cycloalkyl, more preferably, R⁶ and R⁷ are each independently H or—C₁₋₆alkyl.

In some aspects, one of R⁴ and R⁵ is H. In certain of these aspects, theother of R⁴ and R⁵ is —C₁₋₆alk-O—C₁₋₆alkyl, for example,—C₁₋₅alk-O—C₁₋₅alkyl, —C₁₋₄alk-O—C₁₋₄alkyl, —C₁₋₃alk-O—C₁₋₃alkyl,—C₁₋₂alk-O—C₁₋₂alkyl, or —C₁alk-O-C₁alkyl.

In some aspects, one of R⁴ and R⁵ is H. In certain of these aspects, theother of R⁴ and R⁵ is —C₁₋₆alk-NH—C₀₋₆alk-O—C₁₋₆alkyl, for example,—C₁₋₅alk-NH—C₀₋₆alk-O—C₁₋₅alkyl, —C₁₋₄alk-NH—C₀₋₆alk-O—C₁₋₄alkyl,—C₁₋₃alk-NH—C₀₋₆alk-O—C₁₋₃alkyl,—C₁₋₂alk-NH—C₀₋₆alk-O—C₁₋₂alkyl,—C₁alk-NH—C₀₋₆alk-O-C₁alkyl,—C₁₋₅alk-NH—C₀₋₆alk-O—C₁₋₅alkyl, —C₁₋₄alk-NH—C₁₋₅alk-O—C₁₋₄alkyl,—C₁₋₃alk-NH—C₁₋₄alk-O—C₁₋₃alkyl,—C₁₋₂alk-NH—C₁₋₃alk-O—C₁₋₂alkyl,—C₁alk-NH—C₁₋₂alk-O—C₁₋₆alkyl, or—C₁₋₆alk-NH-C₀alk-O—C₁₋₆alkyl.

In some aspects, one of R⁴ and R⁵ is H. In certain of these aspects, theother of R⁴ and R⁵ is —C₁₋₆alk-NHSO₂—C₁₋₆alkyl, for example,—C₁₋₅alk-NHSO₂—C₁₋₅alkyl —C₁₋₄alk-NHSO₂—C₁₋₄alkyl,—C₁₋₃alk-NHSO₂—C₁₋₃alkyl, —C₁₋₂alk-NHSO₂—C₁₋₂alkyl, or—C₁alk-NHSO₂—C₁alkyl.

In some aspects, one of R⁴ and R⁵ is H. In certain of these aspects, theother of R⁴ and R⁵ is —C₁₋₆alk-SO₂—C₁₋₆alkyl, for example,—C₁₋₅alk-SO₂—C₁₋₅alkyl, —C₁₋₄alk-SO₂—C₁₋₄alkyl, —C₁₋₃alk-SO₂—C₁₋₃alkyl,—C₁₋₂alk-SO₂—C₁₋₂alkyl, or —C₁alk-SO₂—C₁alkyl.

In some aspects, one of R⁴ and R⁵ is H. In certain of these aspects, theother of R⁴ and R⁵ is —NHC(O)—C₁₋₆alkyl, for example, —NHC(O)—C₁₋₅alkyl,—NHC(O)—C₁₋₄alkyl, —NHC(O)—C₁₋₃alkyl, —NHC(O)—C₁₋₂alkyl, or—NHC(O)—C₁alkyl.

In some aspects, one of R⁴ and R⁵ is H. In certain of these aspects, theother of R⁴ and R⁵ is linker-PEG-Biotin, preferably

In preferred aspects, one of R⁴ and R⁵ is H and the other of R⁴ and R⁵is C₁₋₆alkyl (e.g., methyl, t-butyl); cycloalkyl (e.g., cyclopropyl);—C₁₋₆alk-NR⁶R⁷ (e.g., —CH₂—NH₂, —CH₂—NHCH₃, —CH₂—N(CH₃)₂, —C(CH₃)₂—NH₂,—C(CH₃)₂—NHCH₃, —C(CH₃)₂—N(CH₃)₂; —C₁₋₆alk-O—C₁₋₆alkyl (e.g.,—C(CH₃)₂—OCH₃, —C(CH₃)₂—OCH₂CH₃); —C₀₋₆alk-heterocycloalkyl substitutedwith —C₁₋₆alkyl (e.g., —C(CH₃)-oxetanyl).

A preferred subgenus of formula I is:

wherein the piperidinyl ring is substituted at the ring nitrogen withany 1 or 2 of the R² substituents defined herein.

Additional embodiments of the disclosure include compounds of Formula(I) having the subgenera of Formula (I-B-1) and Formula (I-B-2):

Within the scope of the disclosure, A can be a bond. Also within thescope of the disclosure, A can be pyridyl; phenyl; napthalenyl;pyrimidinyl; pyrazinyl; pyridazinyl; benzo[d][1,3]dioxolyl optionallysubstituted with halogen, preferably F; benzothiophenyl; or pyrazolyl.Also within the scope of the disclosure, A can be pyridyl; phenyl;napthalenyl; pyrimidinyl; pyrazinyl; pyridazinyl; benzothiophenyl; orpyrazolyl. Also according to the disclosure, any of the A moieties(excluding a bond) can be unsubstituted or substituted with 1, 2, or 3substituents, preferably 1 or 2 substituents, more preferably 1substituent, independently selected from the group consisting of—C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl,or —C₁alkyl; halogen, for example F or Cl; —SF₅; —OC₁₋₆alkyl, forexample, —OC₁₋₅alkyl, —OC₁₋₄alkyl, —OC₁₋₃alkyl, —OC₁₋₂alkyl, or—OC₁alkyl; —C(O)—C₁₋₆alkyl, for example, —C(O)—C₁₋₅alkyl,—C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl, —C(O)—C₁₋₂alkyl, or —C(O)—C₁alkyl; and—C₁₋₆haloalkyl, for example, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl,—C₁₋₃haloalkyl, —C₁₋₂haloalkyl, or —C₁haloalkyl, including —CF₃,—CH₂CH₂F, and the like.

In some aspects, A is pyridyl. The pyridyl can be attached to any of thecompounds of formula I (or its subgenera) through any ring carbon atom,but preferably it attached through the 2- or 3-position carbon.Preferably, the pyridyl is substituted with one or two substituents,preferably one substituent. The pyridyl substituent can be attached toany ring carbon atom of the pyridyl ring. In those embodiments whereinthe pyridyl is attached to the compound of formula I through the3-position carbon, the substituent is preferably attached to the pyridylat the 2- or 4-position. The pyridyl can be substituted at any availablering carbon atom with —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl. The pyridyl can be substituted atany available ring carbon atom with halogen, for example F or Cl. Thepyridyl can be substituted at any available ring carbon atom with —SF₅.The pyridyl can be substituted at any available ring carbon atom with—OC₁₋₆alkyl, for example, —OC₁₋₅alkyl, —OC₁₋₄alkyl, —OC₁₋₃alkyl,—OC₁₋₂alkyl, or —OC₁alkyl. The pyridyl can be substituted at anyavailable ring carbon atom with —C(O)—C₁₋₆alkyl, for example,—C(O)—C₁₋₅alkyl, —C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl, —C(O)—C₁₋₂alkyl, or—C(O)—C₁alkyl. The pyridyl can be substituted at any available ringcarbon atom with —C₁₋₆haloalkyl, for example, —C₁₋₅haloalkyl,—C₁₋₄haloalkyl, —C₁₋₃haloalkyl, —C₁₋₂haloalkyl, or —C₁haloalkyl,including —CF₃, CH₂CH₂F, and the like. Preferred substituents wherein Ais pyridyl include —C₁₋₆alkyl, with —C₁alkyl being most preferred, andwith one —C₁alkyl substituent being more preferred. Other preferredsubstituents include halogen, in particular F and Cl.

In some aspects, A is phenyl. Preferably, the phenyl is substituted withone or two substituents, preferably one substituent. The phenyl can besubstituted at any available ring carbon atom with —C₁₋₆alkyl, forexample, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or -C₁alkyl.The phenyl can be substituted at any available ring carbon atom withhalogen, for example F or Cl. The phenyl can be substituted at anyavailable ring carbon atom with —SF₅.

The phenyl can be substituted at any available ring carbon atom with—OC₁₋₆alkyl, for example, —OC₁₋₅alkyl, —OC₁₋₄alkyl, —OC₁₋₃alkyl,—OC₁₋₂alkyl, or —OC₁alkyl. The phenyl can be substituted at anyavailable ring carbon atom with —C(O)—C₁₋₆alkyl, for example,—C(O)—C₁₋₅alkyl, —C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl, —C(O)—C₁₋₂alkyl, or—C(O)—C₁alkyl. The phenyl can be substituted at any available ringcarbon atom with —C₁₋₆haloalkyl, for example, —C₁₋₅haloalkyl,—C₁₋₄haloalkyl, —C₁₋₃haloalkyl, —C₁₋₂haloalkyl, or —C₁haloalkyl,including —CF₃, CH₂CH₂F, and the like. The phenyl's substituent can beattached to any ring carbon atom of the phenyl ring, preferably ortho tothe phenyl moiety's point of attachment to the compound of formula I.Preferred substituents wherein A is phenyl include —C₁₋₆alkyl, with—C₁alkyl being most preferred. Other preferred substituents includehalogen, in particular F and Cl.

In some aspects, A is napthalenyl. Preferably, the napthalenyl issubstituted with one or two substituents, preferably one substituent.The napthalenyl can be substituted at any available ring carbon atomwith —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl,—C₁₋₂alkyl, or -C₁alkyl. The napthalenyl can be substituted at anyavailable ring carbon atom with halogen, for example F or Cl. Thenapthalenyl can be substituted at any available ring carbon atom with—SF₅. The napthalenyl can be substituted at any available ring carbonatom with —OC₁₋₆alkyl, for example, —OC₁₋₅alkyl, —OC₁₋₄alkyl,—OC₁₋₃alkyl, —OC₁₋₂alkyl, or —OC₁alkyl. The napthalenyl can besubstituted at any available ring carbon atom with —C(O)—C₁₋₆alkyl, forexample, —C(O)—C₁₋₅alkyl, —C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl,—C(O)—C₁₋₂alkyl, or —C(O)—C₁alkyl. The napthalenyl can be substituted atany available ring carbon atom with —C₁₋₆haloalkyl, for example,—C₁₋₅haloalkyl, —C₁₋₄haloalkyl, —C₁₋₃haloalkyl, —C₁₋₂haloalkyl, or—C₁haloalkyl, including —CF₃, CH₂CH₂F, and the like. The napthalenyl canbe attached through any of its carbon atoms to the compound of formulaI. The napthalenyl substituent can be attached to any ring carbon atomof the napthalenyl ring, preferably ortho to the napthalenyl moiety'spoint of attachment to the compound of formula I. Preferred substituentswherein A is napthalenyl include —C₁₋₆alkyl, with —C₁alkyl being mostpreferred. Other preferred substituents include halogen, in particular Fand Cl.

In some aspects, A is pyrimidinyl. The pyrimidinyl can be attached toany of the compounds of formula I (or its subgenera) through any ringcarbon atom through any ring carbon atom. Preferably, the pyrimidinyl issubstituted with one or two substituents, preferably one substituent.The pyrimidinyl can be substituted at any available ring carbon atomwith —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl,—C₁₋₂alkyl, or —C₁alkyl. The pyrimidinyl can be substituted at anyavailable ring carbon atom with halogen, for example F or Cl. Thepyrimidinyl can be substituted at any available ring carbon atom with—SF₅. The pyrimidinyl can be substituted at any available ring carbonatom with —OC₁₋₆alkyl, for example, —OC₁₋₅alkyl, —OC₁₋₄alkyl,—OC₁₋₃alkyl, —OC₁₋₂alkyl, or —OC₁alkyl. The pyrimidinyl can besubstituted at any available ring carbon atom with —C(O)—C₁₋₆alkyl, forexample, —C(O)—C₁₋₅alkyl, —C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl,—C(O)—C₁₋₂alkyl, or —C(O)—C₁alkyl. The pyrimidinyl can be substituted atany available ring carbon atom with —C₁₋₆haloalkyl, for example,—C₁₋₅haloalkyl, —C₁₋₄haloalkyl, —C₁₋₃haloalkyl, —C₁₋₂haloalkyl, or—C₁haloalkyl, including —CF₃, CH₂CH₂F, and the like. Preferredsubstituents wherein A is pyrimidinyl include —C₁₋₆alkyl, with —C₁alkylbeing most preferred. Other preferred substituents include halogen, inparticular F and Cl.

In some aspects, A is pyrazinyl. The pyrazinyl can be attached to any ofthe compounds of formula I (or its subgenera) through any ring carbonatom. Preferably, the pyrazinyl is substituted with one or twosubstituents, preferably one substituent. The pyrazinyl can besubstituted at any available ring carbon atom with —C₁₋₆alkyl, forexample, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl.The pyrazinyl can be substituted at any available ring carbon atom withhalogen, for example F or Cl. The pyrazinyl can be substituted at anyavailable ring carbon atom with —SF₅. The pyrazinyl can be substitutedat any available ring carbon atom with —OC₁₋₆alkyl, for example,—OC₁₋₅alkyl, —OC₁₋₄alkyl, —OC₁₋₃alkyl, —OC₁₋₂alkyl, or —OC₁alkyl. Thepyrazinyl can be substituted at any available ring carbon atom with—C(O)—C₁₋₆alkyl, for example, —C(O)—C₁₋₅alkyl, —C(O)—C₁₋₄alkyl,—C(O)—C₁₋₃alkyl, —C(O)—C₁₋₂alkyl, or —C(O)—C₁alkyl. The pyrazinyl can besubstituted at any available ring carbon atom with —C₁₋₆haloalkyl, forexample, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl, —C₁₋₃haloalkyl, —C₁₋₂haloalkyl,or —C₁haloalkyl, including —CF₃, CH₂CH₂F, and the like. Preferredsubstituents wherein A is pyrazinyl include —C₁₋₆alkyl, with —C₁alkylbeing most preferred. Other preferred substituents include halogen, inparticular F and Cl.

In some aspects, A is pyridazinyl. The pyridazinyl can be attached toany of the compounds of formula I (or its subgenera) through any ringcarbon atom. Preferably, the pyridazinyl is substituted with one or twosubstituents, preferably one substituent. The pyridazinyl can besubstituted at any available ring carbon atom with —C₁₋₆alkyl, forexample, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl.The pyridazinyl can be substituted at any available ring carbon atomwith halogen, for example F or Cl. The pyridazinyl can be substituted atany available ring carbon atom with —SF₅. The pyridazinyl can besubstituted at any available ring carbon atom with —OC₁₋₆alkyl, forexample, —OC₁₋₅alkyl, —OC₁₋₄alkyl, —OC₁₋₃alkyl, —OC₁₋₂alkyl, or—OC₁alkyl. The pyridazinyl can be substituted at any available ringcarbon atom with —C(O)—C₁₋₆alkyl, for example, —C(O)—C₁₋₅alkyl,—C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl, —C(O)—C₁₋₂alkyl, or —C(O)—C₁alkyl. Thepyridazinyl can be substituted at any available ring carbon atom with—C₁₋₆haloalkyl, for example, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl,—C₁₋₃haloalkyl, —C₁₋₂haloalkyl, or —C₁haloalkyl, including —CF₃,CH₂CH₂F, and the like. Preferred substituents wherein A is pyridazinylinclude —C₁₋₆alkyl, with —C₁alkyl being most preferred. Other preferredsubstituents include halogen, in particular F and Cl.

In some aspects, A is benzo[d][1,3]dioxolyl. The benzo[d][1,3]dioxolylcan be attached to any of the compounds of formula I (or its subgenera)through any ring carbon atom. The benzo[d][1,3]dioxolyl can beunsubstituted or can be substituted with one or two halogen, preferablyF. Preferably, the benzo[d][1,3]dioxolyl is substituted with one or twoother substituents. The benzo[d][1,3]dioxolyl can be substituted at anyavailable ring carbon atom with —C₁₋₆alkyl, for example, —C₁₋₅alkyl,—C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl. Thebenzo[d][1,3]dioxolyl can be substituted at any available ring carbonatom with halogen, for example F or Cl. The benzo[d][1,3]dioxolyl can besubstituted at any available ring carbon atom with —SF₅. Thebenzo[d][1,3]dioxolyl can be substituted at any available ring carbonatom with —OC₁₋₆alkyl, for example, —OC₁₋₅alkyl, —OC₁₋₄alkyl,—OC₁₋₃alkyl, —OC₁₋₂alkyl, or —OC₁alkyl. The benzo[d][1,3]dioxolyl can besubstituted at any available ring carbon atom with —C(O)—C₁₋₆alkyl, forexample, —C(O)—C₁₋₅alkyl, —C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl,—C(O)—C₁₋₂alkyl, or —C(O)—C₁alkyl. The benzo[d][1,3]dioxolyl can besubstituted at any available ring carbon atom with —C₁₋₆haloalkyl, forexample, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl, —C₁₋₃haloalkyl, —C₁₋₂haloalkyl,or —C₁haloalkyl, including —CF₃, CH₂CH₂F, and the like.

In some aspects, A is benzothiophenyl. The benzothiophenyl can beattached to any of the compounds of formula I (or its subgenera) throughany ring carbon atom. Preferably, the benzothiophenyl is substitutedwith one or two substituents, preferably one substituent. Thebenzothiophenyl can be substituted at any available ring carbon atomwith —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl,—C₁₋₂alkyl, or —C₁alkyl. The benzothiophenyl can be substituted at anyavailable ring carbon atom with halogen, for example F or Cl. Thebenzothiophenyl can be substituted at any available ring carbon atomwith —SF₅. The benzothiophenyl can be substituted at any available ringcarbon atom with —OC₁₋₆alkyl, for example, —OC₁₋₅alkyl, —OC₁₋₄alkyl,—OC₁₋₃alkyl, —OC₁₋₂alkyl, or —OC₁alkyl. The benzothiophenyl can besubstituted at any available ring carbon atom with —C(O)—C₁₋₆alkyl, forexample, —C(O)—C₁₋₅alkyl, —C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl,—C(O)—C₁₋₂alkyl, or —C(O)—C₁alkyl. The benzothiophenyl can besubstituted at any available ring carbon atom with —C₁₋₆haloalkyl, forexample, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl, —C₁₋₃haloalkyl, —C₁₋₂haloalkyl,or —C₁haloalkyl, including —CF₃, CH₂CH₂F, and the like.

In some aspects, A is pyrazolyl. The pyrazolyl can be attached to any ofthe compounds of formula I (or its subgenera) through any ring carbonatom. Preferably, the pyrazolyl is substituted with one or twosubstituents, preferably one substituent. The pyrazolyl can besubstituted at any available ring carbon atom with —C₁₋₆alkyl, forexample, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl.The pyrazolyl can be substituted at any available ring carbon atom withhalogen, for example F or Cl. The pyrazolyl can be substituted at anyavailable ring carbon atom with —SF₅. The pyrazolyl can be substitutedat any available ring carbon atom with —OC₁₋₆alkyl, for example,—OC₁₋₅alkyl, —OC₁₋₄alkyl, —OC₁₋₃alkyl, —OC₁₋₂alkyl, or —OC₁alkyl. Thepyrazolyl can be substituted at any available ring carbon atom with—C(O)—C₁₋₆alkyl, for example, —C(O)—C₁₋₅alkyl, —C(O)—C₁₋₄alkyl,—C(O)—C₁₋₃alkyl, —C(O)—C₁₋₂alkyl, or —C(O)—C₁alkyl. The pyrazolyl can besubstituted at any available ring carbon atom with —C₁₋₆haloalkyl, forexample, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl, —C₁₋₃haloalkyl, —C₁₋₂haloalkyl,or —C haloalkyl, including —CF₃, CH₂CH₂F, and the like.

In preferred aspects, A is an unsubstituted or substituted phenyl,pyridyl, pyrimidyl, or pyrazinyl moiety, with pyridinyl beingparticularly preferred. In those aspects wherein the phenyl, pyridyl,pyrimidyl, or pyrazinyl moiety is substituted, the preferredsubstituents include —C₁₋₆alkyl (e.g., methyl) and halogen (e.g., F orCl), with methyl being particularly preferred.

Additional embodiments of the disclosure are compounds of Formula (I)having the subgenera of Formula (I-D):

wherein the phenyl moiety can be unsubstituted or substituted with 1 or2 substituents at any available carbon atom.

Additional embodiments of the disclosure are compounds of Formula (I)having the subgenera of Formula (I-E):

wherein the pyridyl moiety can be unsubstituted or substituted with 1 or2 substituents at any available carbon atom.

Additional embodiments of the disclosure are compounds of Formula (I)having the subgenera of Formula (I-F):

wherein the pyridyl moiety can be unsubstituted or substituted with 1 or2 substituents at any available carbon atom.

According to the disclosure, E is —O—; a bond; —C(O)—NH—; —CH₂—; or—CH₂—O—. The E moiety can be attached through any available carbon atomon the A moiety. The E moiety can also be attached through any availablecarbon atom on the G moiety.

In preferred aspects, E is —O—. In other preferred aspects, E is a bond.

In some aspects of the disclosure, E is —C(O)—NH—, wherein the A-E-Gmoiety is A-C(O)—NH-G.

In other aspects of the disclosure, E is —CH₂—.

In yet other aspects of the disclosure, E is —CH₂—O—, wherein the A-E-Gmoiety is A-CH₂—O-G.

Additional embodiments of the disclosure are compounds of Formula (I)having the subgenera of Formula (I-G-1):

wherein the phenyl moiety can be unsubstituted or substituted with 1 or2 substituents at any available carbon atom.

Additional embodiments of the disclosure are compounds of Formula (I)having the subgenera of Formula (I-G-2):

wherein the phenyl moiety can be unsubstituted or substituted with 1 or2 substituents at any available carbon atom.

Additional embodiments of the disclosure are compounds of Formula (I)having the subgenera of Formula (I-H-1):

wherein the pyridyl moiety can be unsubstituted or substituted with 1 or2 substituents at any available carbon atom.

Additional embodiments of the disclosure are compounds of Formula (I)having the subgenera of Formula (I-H-2):

wherein the pyridyl moiety can be unsubstituted or substituted with 1 or2 substituents at any available carbon atom.

Additional embodiments of the disclosure are compounds of Formula (I)having the subgenera of Formula (I-J-1):

wherein the pyridyl moiety can be unsubstituted or substituted with 1 or2 substituents at any available carbon atom.

Additional embodiments of the disclosure are compounds of Formula (I)having the subgenera of Formula (I-J-2):

wherein the pyridyl moiety can be unsubstituted or substituted with 1 or2 substituents at any available carbon atom.

Other preferred subgenera of formula I are:

According to the disclosure, G is H; —C₃₋₆cycloalkyl; -phenyl;-thiophenyl; —C₁₋₆alkyl; -pyrimidinyl; -pyridyl; -pyridazinyl;-benzofuranyl; —C₁₋₆haloalkyl; -heterocycloalkyl that contains an oxygenheteroatom; -phenyl-CH₂—O-phenyl; —C₁₋₆alk-O—C₁₋₆alkyl; —NR⁶R⁷;—SO₂C₁₋₆alkyl; or —OH; wherein the phenyl; pyridyl; pyridazinyl;pyrimidinyl; benzofuranyl; or thiophenyl is optionally substituted with1, 2, or 3 substituents independently selected from the group consistingof halogen; —C₁₋₆alkyl; —C₁₋₆haloalkyl; —OC₁₋₆haloalkyl;—C₃₋₆cycloalkyl; —OC₁₋₆alkyl; —CN; —OH; —C₁₋₆alk-O—C₁₋₆alkyl;—C(O)—NR⁶R⁷; and —C(O)—C₁₋₆alkyl.

In some aspects, G is H.

In other aspects, G is —C₃₋₆cycloalkyl, for example, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl.

In some aspects, G is —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄lkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl.

In some aspects, G is —C₁₋₆haloalkyl, for example, —C₁₋₅haloalkyl,—C₁₋₄haloalkyl, —C₁₋₃haloalkyl, —C₁₋₂haloalkyl, or —C₁haloalkyl,including —CF₃, —CH₂CH₂F, and the like.

In other aspects, G is a -heterocycloalkyl that contains an oxygenheteroatom, for example, tetrahydropyranyl, tetrahydrofuranyl, oroxetanyl.

In preferred aspects, G is -phenyl-CH₂—O-phenyl. In these aspects, the-phenyl-CH₂—O-phenyl can be unsubstituted or substituted with 1, 2, or 3substituents, preferably 1 or 2 substituents, more preferably 1substituent, independently selected from the group consisting ofhalogen; —C₁₋₆alkyl; —C₁₋₆haloalkyl; —OC₁₋₆haloalkyl; —C₃₋₆cycloalkyl;—OC₁₋₆alkyl; —CN; —OH; —C₁₋₆alk-O—C₁₋₆alkyl; —C(O)—NR⁶R⁷ (wherein R⁶ andR⁷ are as previously described herein); and —C(O)—C₁₋₆alkyl. The one orboth of the phenyl rings of the -phenyl-CH₂—O-phenyl moiety can besubstituted with halogen, for example F or Cl. The one or both of thephenyl rings of the -phenyl-CH₂—O-phenyl moiety can be substituted with—C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl,or —C₁alkyl. The one or both of the phenyl rings of the-phenyl-CH₂—O-phenyl moiety can be substituted with —C₁₋₆haloalkyl, forexample, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl, —C₁₋₃haloalkyl, —C₁₋₂haloalkyl,or —C₁haloalkyl. The one or both of the phenyl rings of the-phenyl-CH₂—O-phenyl moiety can be substituted with —OC₁₋₆haloalkyl, forexample, —OC₁₋₅haloalkyl, —OC₁₋₄haloalkyl, —OC₁₋₃haloalkyl,—OC₁₋₂haloalkyl, or -OC₁haloalkyl. The one or both of the phenyl ringsof the -phenyl-CH₂—O-phenyl moiety can be substituted with—C₃₋₆cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. The one or both of the phenyl rings of the-phenyl-CH₂—O-phenyl moiety can be substituted with —OC₁₋₆alkyl, forexample, —OC₁₋₅-alkyl, —OC₁₋₄alkyl, —OC₁₋₃alkyl, —OC₁₋₂alkyl, or-OC₁alkyl. The one or both of the phenyl rings of the-phenyl-CH₂—O-phenyl moiety can be substituted with —CN. The one or bothof the phenyl rings of the -phenyl-CH₂—O-phenyl moiety can besubstituted with —OH. The one or both of the phenyl rings of the-phenyl-CH₂—O-phenyl moiety can be substituted with—C₁₋₆alk-O—C₁₋₆alkyl, for example, —C₁₋₅alk-O—C₁₋₅alkyl,—C₁₋₄alk-O—C₁₋₄alkyl, —C₁₋₃alk-O—C₁₋₃alkyl, —C₁₋₂alk-O—C₁₋₂alkyl, or—C₁alk-O-C₁alkyl. The one or both of the phenyl rings of the-phenyl-CH₂—O-phenyl moiety can be substituted with —C(O)—NR⁶R⁷, whereinR⁶ and R⁷ are preferably each independently H; —C₁₋₆alkyl, for example,—C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl; or—C₃₋₆cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. More preferably, R⁶ and R⁷ are each independently H or—C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl,or —C₁alkyl. The one or both of the phenyl rings of the-phenyl-CH₂—O-phenyl moiety can be substituted with —C(O)—C₁₋₆alkyl, forexample, —C(O)—C₁₋₆₅alkyl, —C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl,—C(O)—C₁₋₂alkyl, or —C(O)—C₁alkyl.

In some aspects, G is —C₁₋₆alk-O—C₁₋₆alkyl, for example,—C₁₋₅alk-O—C₁₋₅alkyl, —C₁₋₄alk-O—C₁₋₄alkyl, —C₁₋₃alk-O—C₁₋₃alkyl,—C₁₋₂alk-O—C₁₋₂alkyl, or —C₁alk-O-C₁alkyl.

In other aspects, G is —NR⁶R⁷, wherein R⁶ and R⁷ are each independentlyH; —C₁₋₆alkyl; —C₃₋₆cycloalkyl; —C(O)H, or —CN. In these aspects, R⁶ andR⁷ are preferably each independently H; —C₁₋₆alkyl, for example,—C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl; or—C₃₋₆cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. More preferably, R⁶ and R⁷ are each independently H or—C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl,or —C₁alkyl.

In some aspects, G is —SO₂C₁₋₆alkyl, for example, —SO₂C₁₋₅alkyl,—SO₂C₁₋₄alkyl, —SO₂C₁₋₃alkyl, —SO₂C₁₋₂alkyl, or —SO₂C₁alkyl.

In some aspects, G is —OH.

In preferred aspects, G is phenyl. In these aspects, the phenyl can beunsubstituted or substituted with 1, 2, or 3 substituents, preferably 1or 2 substituents, more preferably 1 substituent, independently selectedfrom the group consisting of halogen; —C₁₋₆alkyl; —C₁₋₆haloalkyl;—OC₁₋₆haloalkyl; —C₃₋₆cycloalkyl; —OC₁₋₆alkyl; —CN; —OH;—C₁₋₆alk-O—C₁₋₆alkyl; —C(O)—NR⁶R⁷ (wherein R⁶ and R⁷ are as previouslydescribed herein); and —C(O)—C₁₋₆alkyl. The phenyl can be substitutedwith halogen, for example F or Cl. The phenyl can be substituted with—C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl,or —C₁alkyl. The phenyl can be substituted with —C₁₋₆haloalkyl, forexample, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl, —C₁₋₃haloalkyl, —C₁₋₂haloalkyl,or —C₁haloalkyl. The phenyl can be substituted with —OC₁₋₆haloalkyl, forexample, —OC₁₋₅haloalkyl, —OC₁₋₄haloalkyl, —OC₁₋₃haloalkyl,—OC₁₋₂haloalkyl, or —OC₁haloalkyl. The phenyl can be substituted with—C₃₋₆cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. The phenyl can be substituted with —OC₁₋₆alkyl, for example,—OC₁₋₅alkyl, —OC₁₋₄alkyl, —OC₁₋₃alkyl, —OC₁₋₂alkyl, or —OC₁alkyl. Thephenyl can be substituted with —CN. The phenyl can be substituted with—OH. The phenyl can be substituted with —C₁₋₆alk-O—C₁₋₆alkyl, forexample, —C₁₋₅alk-O—C₁₋₅alkyl, —C₁₋₄alk-O—C₁₋₄alkyl,—C₁₋₃alk-O—C₁₋₃alkyl, —C₁₋₂alk-O—C₁₋₂alkyl, or —C₁alk-O-C₁alkyl. Thephenyl can be substituted with —C(O)—NR⁶R⁷, wherein R⁶ and R⁷ arepreferably each independently H; —C₁₋₆alkyl, for example, —C₁₋₅alkyl,—C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl; or —C₃₋₆cycloalkyl, forexample, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Morepreferably, R⁶ and R⁷ are each independently H or —C₁₋₆alkyl, forexample, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or -C₁alkyl.The phenyl can be substituted with —C(O)—C₁₋₆alkyl, for example,—C(O)—C₁₋₆₅alkyl, —C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl, —C(O)—C₁₋₂alkyl, or—C(O)—C₁alkyl.

In some aspects, G is pyridyl. In these aspects, the pyridyl can beunsubstituted or substituted with 1, 2, or 3 substituents, preferably 1or 2 substituents, more preferably 1 substituent, independently selectedfrom the group consisting of halogen; —C₁₋₆alkyl; —C₁₋₆haloalkyl;—OC₁₋₆haloalkyl; —C₃₋₆cycloalkyl; —OC₁₋₆alkyl; —CN; —OH;—C₁₋₆alk-O—C₁₋₆alkyl; —C(O)—NR⁶R⁷ (wherein R⁶ and R⁷ are as previouslydescribed herein); and —C(O)—C₁₋₆alkyl. The pyridyl can be substitutedwith halogen, for example F or Cl. The pyridyl can be substituted with—C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl,or —C₁alkyl. The pyridyl can be substituted with —C₁₋₆haloalkyl, forexample, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl, —C₁₋₃haloalkyl, —C₁₋₂haloalkyl,or —C₁haloalkyl. The pyridyl can be substituted with —OC₁₋₆haloalkyl,for example, —OC₁₋₅haloalkyl, —OC₁₋₄haloalkyl, —OC₁₋₃haloalkyl,—OC₁₋₂haloalkyl, or -OC₁haloalkyl. The pyridyl can be substituted with—C₃₋₆cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. The pyridyl can be substituted with —OC₁₋₆alkyl, forexample, —OC₁₋₅alkyl, —OC₁₋₄alkyl, —OC₁₋₃alkyl, —OC₁₋₂alkyl, or—OC₁alkyl. The pyridyl can be substituted with —CN. The pyridyl can besubstituted with —OH. The pyridyl can be substituted with—C₁₋₆alk-O—C₁₋₆alkyl, for example, —C₁₋₅alk-O—C₁₋₅alkyl,—C₁₋₄alk-O—C₁₋₄alkyl, —C₁₋₃alk-O—C₁₋₃alkyl, —C₁₋₂alk-O—C₁₋₂alkyl, or—C₁alk-O-C₁alkyl. The pyridyl can be substituted with —C(O)—NR⁶R⁷,wherein R⁶ and R⁷ are preferably each independently H; —C₁₋₆alkyl, forexample, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl; or—C₃₋₆cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. More preferably, R⁶ and R⁷ are each independently H or—C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl,or —C₁alkyl. The pyridyl can be substituted with —C(O)—C₁₋₆alkyl, forexample, —C(O)—C₁₋₆₅alkyl, —C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl,—C(O)—C₁₋₂alkyl, or —C(O)—C₁alkyl.

In some aspects, G is pyridazinyl. In these aspects, the pyridazinyl canbe unsubstituted or substituted with 1, 2, or 3 substituents, preferably1 or 2 substituents, more preferably 1 substituent, independentlyselected from the group consisting of halogen; —C₁₋₆alkyl;—C₁₋₆haloalkyl; —OC₁₋₆haloalkyl; —C₃₋₆cycloalkyl; —OC₁₋₆alkyl; —CN; —OH;—C₁₋₆alk-O—C₁₋₆alkyl; —C(O)—NR⁶R⁷ (wherein R⁶ and R⁷ are as previouslydescribed herein); and —C(O)—C₁₋₆alkyl. The pyridazinyl can besubstituted with halogen, for example F or Cl. The pyridazinyl can besubstituted with —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl. The pyridazinyl can be substitutedwith —C₁₋₆haloalkyl, for example, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl,—C₁₋₃haloalkyl, —C₁₋₂haloalkyl, or —C₁haloalkyl. The pyridazinyl can besubstituted with —OC₁₋₆haloalkyl, for example, —OC₁₋₅haloalkyl,—OC₁₋₄haloalkyl, —OC₁₋₃haloalkyl, —OC₁₋₂haloalkyl, or —OC₁haloalkyl. Thepyridazinyl can be substituted with —C₃₋₆cycloalkyl, for example,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The pyridazinyl canbe substituted with —OC₁₋₆alkyl, for example, —OC₁₋₅-alkyl, —OC₁₋₄alkyl,—OC₁₋₃alkyl, —OC₁₋₂alkyl, or -OC₁alkyl. The pyridazinyl can besubstituted with —CN. The pyridazinyl can be substituted with —OH. Thepyridazinyl can be substituted with —C₁₋₆alk-O—C₁₋₆alkyl, for example,—C₁₋₅alk-O—C₁₋₅alkyl, —C₁₋₄alk-O—C₁₋₄alkyl, —C₁₋₃alk-O—C₁₋₃alkyl,—C₁₋₂alk-O—C₁₋₂alkyl, or —C₁alk-O-C₁alkyl. The pyridazinyl can besubstituted with —C(O)—NR⁶R⁷, wherein R⁶ and R⁷ are preferably eachindependently H; —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl; or —C₃₋₆cycloalkyl, for example,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. More preferably, R⁶and R⁷ are each independently H or —C₁₋₆alkyl, for example, —C₁₋₅alkyl,—C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl. The pyridazinyl can besubstituted with —C(O)—C₁₋₆alkyl, for example, —C(O)—C₁₋₆₅alkyl,—C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl, —C(O)—C₁₋₂alkyl, or —C(O)—C₁alkyl.

In some aspects, G is pyrimidinyl. In these aspects, the pyrimidinyl canbe unsubstituted or substituted with 1, 2, or 3 substituents, preferably1 or 2 substituents, more preferably 1 substituent, independentlyselected from the group consisting of halogen; —C₁₋₆alkyl;—C₁₋₆haloalkyl; —OC₁₋₆haloalkyl; —C₃₋₆cycloalkyl; —OC₁₋₆alkyl; —CN; —OH;—C₁₋₆alk-O—C₁₋₆alkyl; —C(O)—NR⁶R⁷ (wherein R⁶ and R⁷ are as previouslydescribed herein); and —C(O)—C₁₋₆alkyl. The pyrimidinyl can besubstituted with halogen, for example F or Cl. The pyrimidinyl can besubstituted with —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl. The pyrimidinyl can be substitutedwith —C₁₋₆haloalkyl, for example, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl,—C₁₋₃haloalkyl, —C₁₋₂haloalkyl, or —C₁haloalkyl. The pyrimidinyl can besubstituted with —OC₁₋₆haloalkyl, for example, —OC₁₋₅haloalkyl,—OC₁₋₄haloalkyl, —OC₁₋₃haloalkyl, —OC₁₋₂haloalkyl, or —OC₁haloalkyl. Thepyrimidinyl can be substituted with —C₃₋₆cycloalkyl, for example,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The pyrimidinyl canbe substituted with —OC₁₋₆alkyl, for example, —OC₁₋₅-alkyl, —OC₁₋₄alkyl,—OC₁₋₃alkyl, —OC₁₋₂alkyl, or -OC₁alkyl. The pyrimidinyl can besubstituted with —CN. The pyrimidinyl can be substituted with —OH. Thepyrimidinyl can be substituted with —C₁₋₆alk-O—C₁₋₆alkyl, for example,—C₁₋₅alk-O—C₁-alkyl, —C₁₋₄alk-O—C₁₋₄alkyl, —C₁₋₃alk-O—C₁₋₃alkyl,—C₁₋₂alk-O—C₁₋₂alkyl, or —C₁alk-O-C₁alkyl. The pyrimidinyl can besubstituted with —C(O)—NR⁶R⁷, wherein R⁶ and R⁷ are preferably eachindependently H; —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl; or —C₃₋₆cycloalkyl, for example,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. More preferably, R⁶and R⁷ are each independently H or —C₁₋₆alkyl, for example, —C₁₋₅alkyl,—C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl. The pyrimidinyl can besubstituted with —C(O)—C₁₋₆alkyl, for example, —C(O)—C₁₋₆₅alkyl,—C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl, —C(O)—C₁₋₂alkyl, or —C(O)—C₁alkyl.

In some aspects, G is benzofuranyl. In these aspects, the benzofuranylcan be unsubstituted or substituted with 1, 2, or 3 substituents,preferably 1 or 2 substituents, more preferably 1 substituent,independently selected from the group consisting of halogen; —C₁₋₆alkyl;—C₁₋₆haloalkyl; —OC₁₋₆haloalkyl; —C₃₋₆cycloalkyl; —OC₁₋₆alkyl; —CN; —OH;—C₁₋₆alk-O—C₁₋₆alkyl; —C(O)—NR⁶R⁷ (wherein R⁶ and R⁷ are as previouslydescribed herein); and —C(O)—C₁₋₆alkyl. The benzofuranyl can besubstituted with halogen, for example F or Cl. The benzofuranyl can besubstituted with —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl. The benzofuranyl can be substitutedwith —C₁₋₆haloalkyl, for example, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl,—C₁₋₃haloalkyl, —C₁₋₂haloalkyl, or —C₁haloalkyl. The benzofuranyl can besubstituted with —OC₁₋₆haloalkyl, for example, —OC₁₋₅haloalkyl,—OC₁₋₄haloalkyl, —OC₁₋₃haloalkyl, —OC₁₋₂haloalkyl, or —OC₁haloalkyl. Thebenzofuranyl can be substituted with —C₃₋₆cycloalkyl, for example,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The benzofuranylcan be substituted with —OC₁₋₆alkyl, for example, —OC₁₋₅-alkyl,—OC₁₋₄alkyl, —OC₁₋₃alkyl, —OC₁₋₂alkyl, or -OC₁alkyl. The benzofuranylcan be substituted with —CN. The benzofuranyl can be substituted with—OH. The benzofuranyl can be substituted with —C₁₋₆alk-O—C₁₋₆alkyl, forexample, —C₁₋₅alk-O—C₁₋₅alkyl, —C₁₋₄alk-O—C₁₋₄alkyl,—C₁₋₃alk-O—C₁₋₃alkyl, —C₁₋₂alk-O—C₁₋₂alkyl, or —C₁alk-O-C₁alkyl. Thebenzofuranyl can be substituted with —C(O)—NR⁶R⁷, wherein R⁶ and R⁷ arepreferably each independently H; —C₁₋₆alkyl, for example, —C₁₋₅alkyl,—C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl; or —C₃₋₆cycloalkyl, forexample, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Morepreferably, R⁶ and R⁷ are each independently H or —C₁₋₆alkyl, forexample, —C₁₋₅alkyl, —C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl.The benzofuranyl can be substituted with —C(O)—C₁₋₆alkyl, for example,—C(O)—C₁₋₆₅alkyl, —C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl, —C(O)—C₁₋₂alkyl, or—C(O)—C₁alkyl.

In some aspects, G is thiophenyl. In these aspects, the thiophenyl canbe unsubstituted or substituted with 1, 2, or 3 substituents, preferably1 or 2 substituents, more preferably 1 substituent, independentlyselected from the group consisting of halogen; —C₁₋₆alkyl;—C₁₋₆haloalkyl; —OC₁₋₆haloalkyl; —C₃₋₆cycloalkyl; —OC₁₋₆alkyl; —CN; —OH;—C₁₋₆alk-O—C₁₋₆alkyl; —C(O)—NR⁶R⁷ (wherein R⁶ and R⁷ are as previouslydescribed herein); and —C(O)—C₁₋₆alkyl. The thiophenyl can besubstituted with halogen, for example F or Cl. The thiophenyl can besubstituted with —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl. The thiophenyl can be substitutedwith —C₁₋₆haloalkyl, for example, —C₁₋₅haloalkyl, —C₁₋₄haloalkyl,—C₁₋₃haloalkyl, —C₁₋₂haloalkyl, or —C₁haloalkyl. The thiophenyl can besubstituted with —OC₁₋₆haloalkyl, for example, —OC₁₋₅haloalkyl,—OC₁₋₄haloalkyl, —OC₁₋₃haloalkyl, —OC₁₋₂haloalkyl, or —OC₁haloalkyl. Thethiophenyl can be substituted with —C₃₋₆cycloalkyl, for example,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The thiophenyl canbe substituted with —OC₁₋₆alkyl, for example, —OC₁₋₅alkyl, —OC₁₋₄alkyl,—OC₁₋₃alkyl, —OC₁₋₂alkyl, or —OC₁alkyl. The thiophenyl can besubstituted with —CN. The thiophenyl can be substituted with —OH. Thethiophenyl can be substituted with —C₁₋₆alk-O—C₁₋₆alkyl, for example,—C₁₋₅alk-O—C₁₋₅alkyl, —C₁₋₄alk-O—C₁₋₄alkyl, —C₁₋₃alk-O—C₁₋₃alkyl,—C₁₋₂alk-O—C₁₋₂alkyl, or —C₁alk-O-C₁alkyl. The thiophenyl can besubstituted with —C(O)—NR⁶R⁷, wherein R⁶ and R⁷ are preferably eachindependently H; —C₁₋₆alkyl, for example, —C₁₋₅alkyl, —C₁₋₄alkyl,—C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl; or —C₃₋₆cycloalkyl, for example,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. More preferably, R⁶and R⁷ are each independently H or —C₁₋₆alkyl, for example, —C₁₋₅alkyl,—C₁₋₄alkyl, —C₁₋₃alkyl, —C₁₋₂alkyl, or —C₁alkyl. The thiophenyl can besubstituted with —C(O)—C₁₋₆alkyl, for example, —C(O)—C₁₋₆₅alkyl,—C(O)—C₁₋₄alkyl, —C(O)—C₁₋₃alkyl, —C(O)—C₁₋₂alkyl, or —C(O)—C₁alkyl.

In preferred aspects, G is unsubstituted or substituted phenyl, pyridyl,pyridizinyl, or pyrazinyl. In those aspects wherein G is substitutedphenyl, pyridyl, pyridizinyl, or pyrazinyl, preferred substituentsinclude C₁₋₆alkyl (e.g., methyl). In other preferred aspects, G isC₁₋₆alkyl (e.g., -isopropyl).

In preferred aspects, G is unsubstituted or substituted phenyl, pyridyl,pyridizinyl, or pyrazinyl and E is —CH₂— or O. In those aspects whereinG is substituted phenyl, pyridyl, pyridizinyl, or pyrazinyl and E is—CH₂— or O, preferred substituents include C₁₋₆alkyl (e.g., methyl). Inother preferred aspects, G is C₁₋₆alkyl (e.g., -isopropyl) and E is—CH₂— or O.

In preferred embodiments, particularly those wherein the compounds areof Formula II′, G is selected from the group consisting ofC₃₋₆cycloalkyl; oxetanyl; tetrahydrofuranyl; tetrahydropyranyl;benzofuran-7-yloxy; pyridyl; pyridyl substituted with CH₃; phenyl;phenyl substituted with one or two members independently selected fromthe group consisting of: halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, OH,OC₁₋₆alkyl, OC₁₋₆haloalkyl, CH₂OCH₃, (C═O)NH₂, and C₃₋₆cycloalkyl; and

In more preferred aspects, G is phenyl or phenyl substituted withC₁₋₆alkyl.

In preferred embodiments, particularly those wherein the compounds areof Formula III′, G-A is selected from the group consisting of

wherein G is phenyl; or phenyl substituted with one or two membersindependently selected from the group consisting of: halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, pyridyl, oxetan-3-yl, andtetrahydro-2H-pyran-4-yl; and R^(a) is H or CH₃. In more preferredaspects, G-A is

wherein G is phenyl, or phenyl substituted with C₁₋₆alkyl.

In preferred embodiments, particularly those wherein the compounds areof Formula IV′, G-E-A is selected from the group consisting of:

where G is selected from the group consisting of: C₁₋₆alkyl,C₃₋₆cycloalkyl, tetrahydro-2H-pyran-4-yl, pyridazin-3-yl, phenyl, andphenyl substituted with F; and R^(a) is H or CH₃. In more preferredaspects, G-E-A is

R^(a) is CH₃; and G is phenyl.

In preferred embodiments, particularly those wherein the compounds areof Formula V′, G is selected from the group consisting of: C₁₋₆alkyl;C₁₋₆haloalkyl; phenyl; phenyl substituted with one or two membersindependently selected from the group consisting of: halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, OC₁₋₆alkyl, OC₁₋₆haloalkyl, (C═O)—C₁₋₆alkyl, SF₅, OH,NH₂, N(CH₃)₂, OCH₂CH₂OCH(CH₃)₂, and SO₂C₁₋₆alkyl; benzo[d][1,3]dioxolyloptionally substituted with Cl; 2-methylpyridin-3-yl;2-isopropylpyridin-4-yl; benzothiophenyl; napthalenyl; and2,2-difluorobenzo[d][1,3]dioxol-5-yl.

Preferred subgenera of formula I include:

wherein the A phenyl is unsubstituted or substituted, preferably with—C₁₋₆alkyl.

wherein the A pyridyl is unsubstituted or substituted, preferably with—C₁₋₆alkyl.

wherein the A pyridyl is unsubstituted or substituted, preferably with—C₁₋₆alkyl.

wherein the A pyridyl is unsubstituted or substituted, preferably with—C₁₋₆alkyl.

wherein the A pyridyl is unsubstituted or substituted, preferably with—C₁₋₆alkyl.

wherein the A pyridyl is unsubstituted or substituted, preferably with—C₁₋₆alkyl.

wherein the A pyridyl is unsubstituted or substituted, preferably with—C₁₋₆alkyl.

In those embodiments of the disclosure wherein the compounds are ofFormula (II′), preferably R^(a) is H or CH₃; n is 1; E is O; G is phenylor phenyl substituted with C₁₋₆alkyl; Ring B is

and R^(c) and R^(f) are (C═O)CH═CH₂; and R^(d) is H.

In those embodiments of the disclosure wherein the compounds are ofFormula (III′), preferably G-A is

G is phenyl, or phenyl substituted with C₁₋₆alkyl;

Ring B is:

and R^(c) and R^(f) are (C═O)CH═CH₂; and R^(d) is H.

In those embodiments of the disclosure wherein the compounds are ofFormula (IV′), preferably G-E-A is

R^(a) is CH₃; G is phenyl;

Ring B is

and R^(c) and R^(f) are (C═O)CH═CH₂.

A further embodiment of the present disclosure is a compound selectedfrom the group consisting of:

-   N-((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5    S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5    S)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-fluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5    S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5    S)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(benzofuran-7-yloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(2,6-difluorophenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(2-ethylphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-fluoro-6-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(benzofuran-7-yloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,    5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,    5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S,E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Chloroacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,EZ)—N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-Hydroxybut-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(4-Cyano-1,4-oxazepan-6-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(cyclohexyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Cyanopiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,    5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(cyclohexyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-13C-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,    5-dihydro-3H-1-thia-3, 5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(But-2-ynoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-4-methyl-4-morpholinopent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-fluoro-6-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(1-propioloylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Fluoroacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Fluoroacryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-cyclopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(2,6-Difluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(But-2-ynoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(2-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-ethyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-4-methyl-4-(tetrahydro-2H-pyran-4-yl)pent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(2,6-difluorophenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-ethoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2,6-difluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(Benzofuran-7-yloxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(3-Methoxypropanoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Ethylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(3-Hydroxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(2-ethylphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2,3-dimethyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-fluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2,6-dimethyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pentafluorothio)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-Tetrahydro-2H-pyran-3-yl    5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2,4-dimethylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(3-methoxypropanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1,6-Dimethylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Isopropylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-4-Fluoro-1-(3-methoxypropanoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Methoxyacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Cyanoazepan-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(3-Hydroxypropanoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Isopropylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1,6-Dimethylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Fluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Acryloylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-13C-Acryloylpiperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((R)-2-Amino-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-4-methyl-4-morpholinopent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(2-hydroxyacetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(2-methoxyacetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,Z)—N-(1-(But-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Isopropylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-ethyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((S)-2-Amino-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridazin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((S)-2-Hydroxy-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Hydroxyacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((S)-1-methylpyrrolidine-3-carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(3-hydroxypropanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(4-Methyl-1,4-oxazepan-6-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(3-(Dimethylamino)propanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((S)-pyrrolidine-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3S,4R)-4-Fluoro-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Chloro-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,Z)—    N-(1-(2-Cyano-4-(dimethylamino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Fluoro-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(oxetane-3-carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-N-methyl-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-5-Fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-4-Hydroxy-1-(3-methoxypropanoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Cyano-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Ethylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((S)-2,3-Dimethoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((R)-2-Hydroxy-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(2-(trifluoromethyl)acryloyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((R)-1-methylpyrrolidine-3-carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-(o-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Cyclopropylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-4-methyl-4-(piperidin-1-yl)pent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxy    phenyl)-4-oxo-4, 5-dihydro-3H-1-thia-3, 5,    8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Aminoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-4-(cyclopropylamino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-((6S)-6-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-4-Fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R)-1-(3-Methoxybutanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((S)-3-Methoxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(2-Ethoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R)-1-(3-Methoxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-5-Fluoro-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propioloylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-(1-methyl-6-oxopiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(3-Aminopropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5S)-5-Fluoro-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1,3-Dimethylpiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(2-oxopiperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5S)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-5-Hydroxy-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(2-Ethylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(quinuclidin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-(3-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-((6R)-6-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(5,5-Difluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2,6-difluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   13C—(R,Z)—N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   13C—(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(cyclohexyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-5-Hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Methyl-4-phenyoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Methylpiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-cyclopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-4-Fluoro-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazepan-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(3-Methoxy-2,2-dimethylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Cyanoazepan-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((R)-2,3-Dimethoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((R)-pyrrolidine-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-ethoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-fluorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,Z)—N-(1-(4-Amino-2-cyano-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(3-(1-Aminocyclopropyl)-2-cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5S)-5-Hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((R)-tetrahydrofuran-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(3-Cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-4-Hydroxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(2-Cyclopropylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1,2-Dimethylpiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Methacryloylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-(Cyclopropanecarbonyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazepan-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((S)-tetrahydrofuran-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-4-Methoxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-(m-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-4-Methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-4-(ethylamino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,    5-dihydro-3H-1-thia-3, 5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Cyclopropylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(3-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Fluoro-4-phenoxyphenyl)-N-(1-(3-methoxypropanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(2-(2-oxoimidazolidin-1-yl)ethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-4-Fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(2-Hydroxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(3-Ethoxyacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Fluoro-6-methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(2-Isopropylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-5-Methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-methylbut-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(3-(Methoxymethyl)phenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-(2-(trifluoromethoxy)phenoxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R,Z)—N-(1-(3-Cyclopropyl-2-fluoroacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Cyclopropylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,EZ)—N-(1-(2-Cyano-3-methoxyacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(*S)-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-(2-cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,EZ)—N-(1-(2-Cyano-4-((2-methoxy    ethyl)amino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2,6-Difluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-4-Hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   N1-((E)-4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)-N5-(15-oxo-19-((3    aS,4R,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,    10-trioxa-14-azanonadecyl)glutaramide;-   (R,E)-N-(1-(2-Cyano-4-methyl-4-(methylamino)pent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,    5-dihydro-3H-1-thia-3, 5, 8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-(2-cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)azetidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-4-Hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-(2-(trifluoromethyl)phenoxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3S,4S)-4-Hydroxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3S,4S)-4-Methoxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3S,4S)-4-Methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-(3-Methoxypropanoyl)azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-methylpent-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazetidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(Cyclohexyloxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Ethylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(Azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-fluorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-chlorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-phenyl-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-(2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-5-Methoxy-1-methylpiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,Z)—N-(1-(2-Fluorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Methyl-5-oxopyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Fluoro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pentafluorothio)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(2-Methyl-4-phenoxyphenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5S)-5-Hydroxy-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5S)-5-Methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-2-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(p-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(5,5-Difluoro-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Isopropylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4,4-Dimethylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-(2-morpholinoethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-2-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,Z)—N-(1-(2-Chlorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenoxy-2-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(m-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Chloro-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2,3-Dimethyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(2-Isopropoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Cyclobutoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(3,5-Difluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Dimethylamino)acetyl)piperidin-3-yl)    5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3, 5,    8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-(p-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(2-Methyl-4-phenoxyphenyl)-N-(2-(3-methylmorpholino)ethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5    (*R)(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-(pyridin-3-yloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-chlorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(4-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-N-(2-(3-methylmorpholino)ethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(Cyclopentyloxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*R)-(2-Methyl-4-phenyoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-fluorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(2,4-Difluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(5-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2,4-dimethylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(5-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-(pyridin-2-yloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(5-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-Benzyl-2-oxoazepan-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-2-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(6-phenoxypyridazin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5    S)-5-Methoxy-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,EZ)—N-(1-(3-Cyclopropyl-2-(trifluoromethyl)acryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-(2-morpholino-2-oxoethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2,6-Dimethyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(3-Hydroxypropanoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Ethylpiperidin-3-yl)-5-(4-(2-isopropylphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Cyclopropoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(*R)-(2-Methy-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxy-2-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(2-Carbamoylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-2-(piperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;-   (R)-6-Methyl-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Cyanopiperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3,5-Dichlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-Methyl-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Isopropoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Ethoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(tert-butyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Chlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-phenyl-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-Methyl-5-(2-methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Methoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-N-(piperidin-3-yl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Methoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*R)-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-([1,1′-Biphenyl]-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3,4-Dichlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-phenyl-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Methylpiperidin-3-yl)-4-oxo-5-(4-phenoxy-2-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Methyl-6-phenoxypyridazin-3-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-methyl-6-phenoxypyridazin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Methylpiperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*R)-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-(pyridin-4-yloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-(Dimethylamino)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-isopropyl-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3,4-dichlorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-Isopropyl-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(3-Methoxy-3-methylbutanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,Z)—N-(1-(3-Acetamidoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Chloroacryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(vinylsulfonyl)pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-trideuteriomethylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(vinylsulfonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylsulfonyl)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-N-(1-(trideuteriomethyl)piperidin-3-yl)-4-oxo-4,    5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-Aminobut-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylsulfonamido)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-(Dimethylamino)acetyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyanobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((S)-Azetidine-2-carbonyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,Z)—N-(1-(2-Fluoro-4-(methylamino)but-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(2-(pyrrolidin-1-yl)acetyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-2-(((1-Acryloylpiperidin-3-yl)amino)methyl)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Aminoacetyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(2-(piperidin-1-yl)acetyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-morpholinoacetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Chloroacetyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Chloroacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(thiophen-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(3-Cyclopropyl-2-methylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,EZ)—N-(1-(2-Chloro-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-morpholinobut-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(benzo[b]thiophen-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Isopropoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-N-(piperidin-3-yl)-5-(4-(thiophen-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenoxybenzyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Methylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxybenzyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(Benzo[b]thiophen-5-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Methylpiperidin-3-yl)-4-oxo-5-(4-phenoxybenzyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(4-phenoxybenzyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-(trifluoromethoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-N-(piperidin-3-yl)-5-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(naphthalen-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(1-benzyl-1H-pyrazol-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-benzylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-([1,1′-Biphenyl]-4-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-(Dimethylamino)acetyl)pyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-([1,1′-Biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(benzo[b]thiophen-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(Benzo[b]thiophen-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(Naphthalen-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Benzylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(1-Benzyl-1H-pyrazol-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-((4*S)-2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-((4*S)-2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-((4*R)-2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-((4*R)-2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-N-methyl-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-N-methyl-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-isopropyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Isopropyl-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Isopropyl-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,*Z)—N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,*Z)—N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,*E)-N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,*E)-N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((1-Acryloylpyrrolidin-3-yl)methyl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   4-Oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(1H-Imidazole-1-carbonyl)piperidin-3-yl)-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methoxy-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-cyclobutoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-cyclobutoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   4-Oxo-N-(2-oxopiperidin-3-yl)-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Methoxy-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Chloro-4-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Methyl-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   4-Oxo-5-(4-phenoxyphenyl)-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-4-Hydroxypyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Benzylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(3-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5    S)-5-Methoxypiperidin-3-yl)-S-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5 S)-5-Methoxypiperidin-3    yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (*S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (*S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (*R)-5    (*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (*R)-5    (*R)-(2-Methy-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,*E)-N-(1-(But-2-enoyl)piperidin-3-yl)-S-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,*E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,*Z)—N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,*Z)-N-(1-(But-2-enoyl)piperidin-3-yl)-S-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,*Z)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,*E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,    5-dihydro-3H-1-thia-3, 5, 8-triazaacenaphthylene-2-carboxamide;-   (R,*Z)—N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,*E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5S)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5S)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(4-Cyano-1,4-oxazepan-6-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3S,4S)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)pyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Methoxyacetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Acryloylazetidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-methyl-5-phenoxypyridin-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′,3′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3′-fluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-cyclobutoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-S-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-3-yl)-S-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3′-chloro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R,EZ)—N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′-chloro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,    5-dihydro-3H-1-thia-3, 5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-benzylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3′-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-Acryloylpyrrolidin-3-yl)-S-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclohexylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-Aminobut-2-enoyl)pyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-S-(4′-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-Hydroxybut-2-enoyl)pyrrolidin-3-yl)-S-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   5-(*S)-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((S)-2-(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenylpyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyrazin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-isopropylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(vinylsulfonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-acryloylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylsulfonamido)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-propylphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclobutylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-trideuteriomethylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenylpyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(pyridin-3-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(Ethylsulfonyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(pyridin-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Isopropylpiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3S,4S)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)pyrrolidine-3-carboxamide;-   (R)-1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)pyrrolidine-3-carboxamide;-   (R)—N-(1-(2-(Methylamino)acetyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((S)-3-Hydroxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,Z)—N-(1-(4-Amino-2-fluorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,Z)—N-(1-(4-Amino-2-chlorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3′-Methyl-[1,    1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2′-Methyl-[1,    1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((E)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoyl)pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2-phenoxypyrimidin-5-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(3-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(cyclohexyloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(cyclopentyloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((R)-3-Hydroxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Acetylphenyl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclopropylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((R)-3-Methoxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(2-(dimethylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(cis)-1-Acryloyl-3-hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Methoxyacetyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Chloro-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   4-Oxo-N-(6-oxopiperidin-3-yl)-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-4-Fluoropyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4′-Methyl-[1,    1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Chloro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acetylpiperidin-3-yl)-5-(3-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-chloro-4-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(2-phenylpyridin-4-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-5-Hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4S)-4-Methoxypyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-cyclobutylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Cyanopiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(3-Methoxypropanoyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Cyanopiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Methyl-5-phenoxypyridin-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-(3-Methoxypropanoyl)piperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-3-amino-4-((3-cyclobutoxyphenyl)amino)thieno[2,3-b]pyridine-2-carboxamide;-   (R)-5-([1,1′-Biphenyl]-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   2-((1-Acryloylpiperidin-3-yl)amino)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;-   (R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(2-(methylamino)acetyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(2-phenylpyridin-4-yl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Cyclobutylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenylpyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Cyclobutoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   2-((1-Acryloylpiperidin-4-yl)amino)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(4-Isopropoxy-2-methylphenyl)-4-oxo-N—((R)-1-((E)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-cyclobutoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(4-phenylpyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (3R,5R)-tert-Butyl    3-hydroxy-5-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(oxetan-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-(Cyclopentyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(trans-3-Hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-(Cyclohexyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   trans-tert-Butyl    3-hydroxy-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;-   (R)-4-Oxo-5-(5-phenylpyridin-3-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Cyclobutoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(pyridin-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(6-phenylpyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5    (*R)-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (3 S,4S)-tert-Butyl    3-fluoro-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidine-1-carboxylate;-   (R)-5-(4-Cyclobutoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   tert-Butyl    4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;-   (R)-tert-Butyl    3-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;-   (R)-5-(3-Cyclohexylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Isopropylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(pyridin-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(oxetan-3-yl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropoxy-3-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Cyclobutylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(tert-butyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (3 S,4S)-tert-Butyl    3-methoxy-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidine-1-carboxylate;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(5-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(tert-butylsulfonyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Hydroxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Acetylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(5-Isopropoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(6-phenoxypyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-(tert-Butyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(pyridin-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-tert-Butyl    3-(5-(3-(tert-butyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;-   (R)-tert-Butyl    3-(5-(3-acetylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;-   (R)-5-(4-(tert-Butylsulfonyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-tert-Butyl    3-(5-(4-(tert-butylsulfonyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;-   (R)-tert-Butyl    3-(5-(4-(tert-butoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;-   (R)-tert-Butyl    3-(5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;-   (R)-tert-Butyl    3-(5-(6-cyclobutoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;-   N-((3R,4R)-1-Acryloyl-4-hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Methyl-5-phenoxypyrazin-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-methyl-5-phenoxypyrazin-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,4R)-4-Hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(cis-3-Hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   4-Oxo-N-(2-oxopyrrolidin-3-yl)-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(R)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(4-methyl-2-phenoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyrimidin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3    yl)-5-(*R)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   N-(cis-4-Acrylamidotetrahydrofuran-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-S-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2′,3′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2′,3′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(3-methyl-2-phenylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-cyclohexylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenylpyridazin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3R,5S)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2′,3′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(6-phenoxypyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((*E)-3-((S)-1-Acetylpyrrolidin-2-yl)-2-cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-cyclobutoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((E)-3-((R)-1-Acetylpyrrolidin-2-yl)-2-cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((E)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenylpyrimidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-isobutylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-cyclopentylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(cyclopentyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(5-methyl-2-phenylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(2-isopropoxyethoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-isopropylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-phenoxypyrazin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-cyclobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-([2,3′-Bipyridin]-4-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(4-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,    5-dihydro-3H-1-thia-3, 5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(3-isopropylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2′,3′-Difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((1    RS,2RS)-2-Aminocyclopentyl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(tetrahydro-2H-pyran-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-([2,2′-Bipyridin]-4-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2′,3′-Difluoro-[1,1′-biphenyl]-3-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(trans-1-Acryloyl-3-hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(Methylglycyl)piperidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,    5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(4-Methyl-2-phenoxypyrimidin-5-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3    S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(5-phenoxypyrimidin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Cyclopentylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Isobutylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(6-phenylpyrimidin-4-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(4-methyl-2-phenoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-cyclobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Isopropylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*R)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(5-Methyl-2-phenylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(2-Isopropoxyethoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Cyclohexylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-isopropoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(3-Methyl-2-phenylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-phenylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-6-phenylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-cyclobutoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(3-methyl-2-phenylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(tetrahydro-2H-pyran-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-tert-Butyl    3-(4-oxo-5-(3-(tetrahydro-2H-pyran-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;-   (R)-4-Oxo-5-(6-phenylpyridazin-4-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(6-phenoxypyridin-3-yl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-tert-Butyl    3-(5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;-   (R)-5-(6-Cyclobutoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((3*S,4*R)-4-Acrylamidotetrahydrofuran-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,    5-dihydro-3H-1-thia-3, 5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-methyl-2-phenoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(2-phenoxypyrimidin-5-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-phenoxypyrimidin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isobutylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenylpyridazin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-((*3R,*4S)-4-Acrylamidotetrahydrofuran-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isopropoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Isobutylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(5-phenylpyridazin-3-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isopropoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(6-Isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*R)-(6-Isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(6-(Cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*R)-(6-(Cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(4-Methyl-2-phenoxypyrimidin-5-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-isobutyl-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-4-oxo-4,    5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-S-(2-methyl-4-((6-methylpyridin-2-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,    5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(5-(2-fluorophenoxy)pyridin-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5S)-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N1-(15-Oxo-19-((3    aR,4R,6aS)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,    10-trioxa-14-azanonadecyl)-N5-((E)-4-oxo-4-(3-(4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)but-2-en-1-yl)glutaramide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,EZ)—N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,    5-dihydro-3H-1-thia-3, 5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-((5-methylpyridin-2-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutyl-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(6-Isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   2-(4-Acryloylpiperazin-1-yl)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;-   (R)-5-(*S)-(6-(Cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(6-Isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acetylpiperidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-1-(2-Cyano-3-cyclopropylacryloyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;-   1-Cyano-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)-1-propionylpiperidine-4-carboxamide;-   (R)-5-(*R)-(6-Isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-N-(1-propionylpiperidin-3-yl)-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acetylpiperidin-3-yl)-4-oxo-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acetylpiperidin-3-yl)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acetylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutyl-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro    3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-1-(2-Cyano-4,4-dimethylpent-2-enoyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;-   1-(2-Cyanoacetyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;-   N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)-1-propionylpiperidine-3-carboxamide;-   1-(2-Cyanoacetyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;-   1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;-   1-Ethyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;-   1-Cyano-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;-   1-Methyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-2-(4-methylpiperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;-   (E)-4,4-Dimethyl-2-(4-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperazine-1-carbonyl)pent-2-enenitrile;-   4-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperazine-1-carbonitrile;-   5-(2-Methyl-4-phenoxyphenyl)-2-(4-propionylpiperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;-   N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;-   (E)-1-(2-Cyano-4,4-dimethylpent-2-enoyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;-   (E)-1-(2-Cyano-3-cyclopropylacryloyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;-   1-Methyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;-   1-Ethyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;-   N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;-   (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(vinylsulfonyl)pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-fluoro-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Cyanopyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Cyanoacetyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(3-Methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′,3′-difluoro-4-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(4-(pyrrolidin-1-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((R)-2-(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N—((R)-1-((R)-Azetidine-2-carbonyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((S)-2-(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-N-(1-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(4-(pyrrolidin-1-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Cyanopiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((R)-pyrrolidine-2-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-Formylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Cyanopiperidin-3-yl)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Cyanopiperidin-4-yl)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Formylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,    5, 8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acetylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((S)-pyrrolidine-2-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(4-(piperidin-1-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-3-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-fluoro-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,    5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(3-Chloropropanoyl)piperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-(2-(Azetidin-1-yl)acetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   4-Oxo-5-(4-phenoxyphenyl)-N-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Methylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Benzoylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(5-phenoxypyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(Cyclopentyloxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Methylpiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-5-(6-phenoxypyridin-3-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Isopropoxy-2-methylphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-Acetylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Benzylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   4-Oxo-5-(4-phenoxyphenyl)-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   4-Oxo-5-(4-phenoxyphenyl)-N-(2-(pyrrolidin-1-yl)ethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   4-Oxo-5-(4-phenoxyphenyl)-N-(2-(piperazin-1-yl)ethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-Acryloylpiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-Methylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   4-Oxo-5-(4-phenoxyphenyl)-N-(2-(piperidin-1-yl)ethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(2-Morpholinoethyl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)-4-Oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(2-(4-Methylpiperazin-1-yl)ethyl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acetylpiperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(pyridin-3-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-Benzoylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3,5-dichlorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(dimethylamino)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N-(1-(2-Cyanoacetyl)piperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S)—N-(1-Benzylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,    5-dihydro-3H-1-thia-3, 5, 8-triazaacenaphthylene-2-carboxamide;-   5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-aminophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(Dimethylamino)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-N-(piperidin-3-yl)-5-(m-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Chlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-4-Oxo-N-(piperidin-3-yl)-5-(p-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Fluorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-(tert-Butyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Isopropoxy-3-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(4-Aminophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-3-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)-5-(*S)-(6-Isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-(1-methylcyclobutyl)acryloyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,    5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   N1-((F)-4-((R)-3-(1-(2-Methyl-6-phenoxypyridin-3-yl)-2-oxo-1,2,3,5-tetrahydrocyclopenta[de]quinazoline-4-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)-N5-(15-oxo-19-((3aR,4R,6aS)-2-oxooctahydrocyclopenta[d]imidazol-4-yl)-4,7,    10-trioxa-14-azanonadecyl)glutaramide;-   (R,E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1    Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-(pyridazin-3-yloxy)pyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-(pyridazin-3-yloxy)pyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-6-(pyridazin-3-yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-(pyridazin-3-yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;-   (R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-6-(pyridazin-3-yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;    and-   (R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-methyl-6-(pyridazin-3-yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;    and

stereoisomers or isotopic variants thereof; and pharmaceuticallyacceptable salts thereof.

The disclosure also relates to methods of using the compounds describedherein to treat subjects diagnosed with or suffering from a disease,disorder, or condition mediated by Bruton's tyrosine kinase. Thesemethods are accomplished by administering to the subject a compound ofthe disclosure in an amount sufficient to inhibit Bruton's tyrosinekinase.

In a further aspect, provided herein are methods for inhibiting Bruton'styrosine kinase in a subject in need of treatment by administering tothe subject a composition containing a therapeutically effective amountof at least one compound of Formula (I)(as well as Formula (I′), Formula(II′), Formula (III′), Formula (IV′) and Formula (V′)). Some aspects ofthe disclosure are directed to methods of treating a subject sufferingfrom an autoimmune disease by administering to the subject a compositioncontaining a therapeutically effective amount of at least one compoundof Formula (I)(as well as Formula (I′), Formula (II′), Formula (III′),Formula (IV′) and Formula (V′)). In some aspects, the autoimmune diseaseis, e.g., inflammatory bowel disease, arthritis, lupus, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome,multiple sclerosis, Guillain-Barré syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitisis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behçet's disease,chronic fatigue, dysautonomia, endometriosis, interstitial cystitis,neuromyotonia, scleroderma, or vulvodynia. When used for the treatmentof an autoimmune disease, the compounds of Formula (I)(as well asFormula (I′), Formula (II′), Formula (III′), Formula (IV′) and Formula(V′)) can be administered as single agents. Alternatively, when used forthe treatment of an autoimmune disease, the compounds of Formula (I)(aswell as Formula (I′), Formula (II′), Formula (III′), Formula (IV′) andFormula (V′)) can be administered in combination with other agents knownto be useful for the treatment of autoimmune diseases.

Other embodiments of the disclosure are directed to methods of treatinga subject suffering from a heteroimmune condition by administering tothe subject a composition containing a therapeutically effective amountof at least one compound of Formula (I)(as well as Formula (I′), Formula(II′), Formula (III′), Formula (IV′) and Formula (V′)). In some aspects,the heteroimmune condition or disease is, e.g., graft versus hostdisease, transplantation, transfusion, anaphylaxis, allergy, type Ihypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopicdermatitis. When used for the treatment of a heteroimmune condition, thecompounds of Formula (I)(as well as Formula (I′), Formula (II′), Formula(III′), Formula (IV′) and Formula (IV′)) can be administered as singleagents. Alternatively, when used for the treatment of a heteroimmunecondition, the compounds of Formula (I)(as well as Formula (I′), Formula(II′), Formula (III′), Formula (IV′) and Formula (V′)) can beadministered in combination with other agents known to be useful for thetreatment of heteroimmune diseases.

Other embodiments of the disclosure are directed to methods of treatinga subject suffering from an inflammatory disease by administering to thesubject a composition containing a therapeutically effective amount ofat least one compound of Formula (I)(as well as Formula (I′), Formula(II′), Formula (III′), Formula (IV′) and Formula (V′)). In certainembodiments, the inflammatory disease is, e.g., asthma, appendicitis,blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, colitis, conjunctivitis, cystitis,dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis,endometritis, enteritis, enterocolitis, epicondylitis, epididymitis,fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis,hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitismyocarditis, myositis, nephritis, oophoritis, orchitis, osteitis,otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.When used for the treatment of an inflammatory disease, the compounds ofFormula (I)(as well as Formula (I′), Formula (II′), Formula (III′),Formula (IV′) and Formula (V′)) can be administered as single agents.Alternatively, when used for the treatment of an inflammatory disease,the compounds of Formula (I)(as well as Formula (I′), Formula (II′),Formula (III′), Formula (IV′) and Formula (V′)) can be administered incombination with other agents known to be useful for the treatment ofinflammatory diseases.

Other embodiments of the disclosure are directed to methods of treatinga subject suffering from cancer by administering to the subject acomposition containing a therapeutically effective amount of at leastone compound of Formula (I)(as well as Formula (I′), Formula (II′),Formula (III′), Formula (IV′) and Formula (V′)). In one embodiment, thecancer is a B-cell proliferative disorder, e.g., diffuse large B celllymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chroniclymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma,plasma cell myeloma, plasmacytoma, extranodal marginal zone B celllymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma,mediastinal (thymic) large B cell lymphoma, intravascular large B celllymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, orlymphomatoid granulomatosis. Cancers that are particularly suited tobeing treated with compounds of the disclosure include mantle celllymphoma and chronic lymphocytic leukemia and macroglobulinemia, as wellas multiple myeloma. In some embodiments, where the subject is sufferingfrom a cancer, an anti-cancer agent is administered to the subject inaddition to one of the above-mentioned compounds. In one embodiment, theanti-cancer agent is an inhibitor of mitogen-activated protein kinasesignaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886,SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002. When used forthe treatment of cancer, the compounds of Formula (I)(as well as Formula(I′), Formula (II′), Formula (III′), Formula (IV′) and Formula (V′)) canbe administered as single agents. Alternatively, when used for thetreatment of cancer, the compounds of Formula (I)(as well as Formula(I′), Formula (II′), Formula (III′), Formula (IV′) and Formula (V′)) canbe administered in combination with other agents known to be useful forthe treatment of cancer.

Other embodiments of the disclosure are directed to methods of treatinga subject suffering from a thromboembolic disorder by administering tothe subject a composition containing a therapeutically effective amountof at least one compound of Formula (I)(as well as Formula (I′), Formula(II′), Formula (III′), Formula (IV′) and Formula (V′)). In furtherembodiments, thromboembolic disorder is, e.g., myocardial infarct,angina pectoris, reocclusion after angioplasty, restenosis afterangioplasty, reocclusion after aortocoronary bypass, restenosis afteraortocoronary bypass, stroke, transitory ischemia, a peripheral arterialocclusive disorder, pulmonary embolism, or deep venous thrombosis. Whenused for the treatment of a thromboembolic disorder, the compounds ofFormula (I)(as well as Formula (I′), Formula (II′), Formula (III′),Formula (IV′) and Formula (V′)) can be administered as single agents.Alternatively, when used for the treatment of a thromboembolic disorder,the compounds of Formula (I)(as well as Formula (I′), Formula (II′),Formula (III′), Formula (IV′) and Formula (V′)) can be administered incombination with other agents known to be useful for the treatment ofthromboembolic disorders.

Other embodiments of the disclosure are directed to methods of treatinga subject suffering from a respiratory disease by administering to thesubject a composition containing a therapeutically effective amount ofat least one compound of Formula (I)(as well as Formula (I′), Formula(II′), Formula (III′), Formula (IV′) and Formula (V′)). In some aspects,the respiratory disease is asthma. In a further embodiment of thisaspect, the respiratory disease includes, but is not limited to, adultrespiratory distress syndrome and allergic (extrinsic) asthma,non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma,clinical asthma, nocturnal asthma, allergen-induced asthma,aspirin-sensitive asthma, exercise-induced asthma, isocapnichyperventilation, child-onset asthma, adult-onset asthma, cough-variantasthma, occupational asthma, steroid-resistant asthma, seasonal asthma.When used for the treatment of a respiratory disease, the compounds ofFormula (I)(as well as Formula (I′), Formula (II′), Formula (III′),Formula (IV′) and Formula (V′)) can be administered as single agents.Alternatively, when used for the treatment of a respiratory disease, thecompounds of Formula (I)(as well as Formula (I′), Formula (II′), Formula(III′), Formula (IV′) and Formula (V′)) can be administered incombination with other agents known to be useful for the treatment ofrespiratory diseases.

In another aspect are methods for preventing rheumatoid arthritis andosteoarthritis comprising administering to the subject, at least once,an effective amount of at least one compound of Formula (I)(as well asFormula (I′), Formula (II′), Formula (III′), Formula (IV′) and Formula(V′)). When used for the treatment of rheumatoid arthritis orosteoarthritis, the compounds of Formula (I) can be administered assingle agents. Alternatively, when used for the treatment of rheumatoidarthritis or osteoarthritis, the compounds of Formula (I)(as well asFormula (I′), Formula (II′), Formula (III′), Formula (IV′) and Formula(V′)) can be administered in combination with other agents known to beuseful for the treatment of rheumatoid arthritis or osteoarthritis.

In another aspect are methods for treating inflammatory responses of theskin comprising administering to the subject, at least once, aneffective amount of at least one compound of Formula (I)(as well asFormula (I′), Formula (II′), Formula (III′), Formula (IV′) and Formula(V′)). Such inflammatory responses of the skin include, by way ofexample, dermatitis, contact dermatitis, eczema, urticaria, rosacea, andscarring. In another aspect are methods for reducing psoriatic lesionsin the skin, joints, or other tissues or organs, comprisingadministering to the mammal an effective amount of a compound of Formula(I)(as well as Formula (I′), Formula (II′), Formula (III′), Formula(IV′) and Formula (V′)). When used for the treatment of theseconditions, the compounds of Formula (I)(as well as Formula (I′),Formula (II′), Formula (III′), Formula (IV′) and Formula (V′)) can beadministered as single agents. Alternatively, when used for thetreatment of these conditions, the compounds of Formula (I)(as well asFormula (I′), Formula (II′), Formula (III′), Formula (IV′) and Formula(V′)) can be administered in combination with other agents known to beuseful for the treatment of these conditions.

In preferred aspects, compounds of the disclosure can be used to treatrheumatoid arthritis.

Compounds of the disclosure can also be used to treat systemic lupuserythematosus.

Compounds of the disclosure can also be used to treat pemphigusdisorders and pemphigoid disorders.

In some aspects, the compounds of Formula (I)(as well as Formula (I′),Formula (II′), Formula (III′), Formula (IV′) and Formula (V′)) can beadministered in combination with a CYP 3A4 inhibitor, according tomethods known in the art.

In treatment methods according to the disclosure, an effective amount ofa pharmaceutical agent according to the disclosure is administered to asubject suffering from or diagnosed as having such a disease, disorder,or condition. An “effective amount” means an amount or dose sufficientto generally bring about the desired therapeutic benefit in patients inneed of such treatment for the designated disease, disorder, orcondition. Effective amounts or doses of the compounds of the presentdisclosure may be ascertained by routine methods such as modeling, doseescalation studies or clinical trials, and by taking into considerationroutine factors, e.g., the mode or route of administration or drugdelivery, the pharmacokinetics of the compound, the severity and courseof the disease, disorder, or condition, the subject's previous orongoing therapy, the subject's health status and response to drugs, andthe judgment of the treating physician. An example of a dose is in therange of from about 0.001 to about 200 mg of compound per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g.,BID, TID, QID). For a 70-kg human, an illustrative range for a suitabledosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about2.5 g/day.

In addition, the compounds of the disclosure may be used in combinationwith additional active ingredients in the treatment of the aboveconditions. The additional active ingredients may be coadministeredseparately with a compound of the disclosure or included with such anagent in a pharmaceutical composition according to the disclosure. Thecombination may serve to increase efficacy (e.g., by including in thecombination a compound potentiating the potency or effectiveness of anactive agent according to the disclosure), decrease one or more sideeffects, or decrease the required dose of the active agent according tothe disclosure.

The compounds of the disclosure are used, alone or in combination withone or more additional active ingredients, to formulate pharmaceuticalcompositions of the disclosure. A pharmaceutical composition of thedisclosure comprises: (a) an effective amount of at least one compoundin accordance with the disclosure; and (b) a pharmaceutically acceptableexcipient.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the compounds of the disclosure can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the compounds may beformulated to yield a dosage of, e.g., from about 0.05 to about 100mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about0.1 to about 10 mg/kg daily. For example, a total daily dosage of about5 mg to 5 g daily may be accomplished by dosing once, twice, three, orfour times per day.

Oral tablets may include a compound according to the disclosure mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservative agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquidoral excipients include ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the disclosure may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the disclosure with water, anoil such as peanut oil or olive oil, liquid paraffin, a mixture of monoand di-glycerides of short chain fatty acids, polyethylene glycol 400,or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this disclosure may also be administered bynon-oral routes. For example, the compositions may be formulated forrectal administration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, thecompounds of the disclosure may be provided in sterile aqueous solutionsor suspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms will be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses may rangefrom about 1 to 1000.mu.g/kg/minute of compound, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compounds of thedisclosure may utilize a patch formulation to affect transdermaldelivery.

Compounds of the disclosure may alternatively be administered in methodsof this disclosure by inhalation, via the nasal or oral routes, e.g., ina spray formulation also containing a suitable carrier.

Exemplary compounds useful in methods of the disclosure will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I)(as well as Formula (I′),Formula (II′), Formula (III′), Formula (IV′) and Formula (IV′)).Reactions may be performed between the melting point and the refluxtemperature of the solvent, and preferably between 0° C. and the refluxtemperature of the solvent. Reactions may be heated employingconventional heating or microwave heating. Reactions may also beconducted in sealed pressure vessels above the normal reflux temperatureof the solvent.

Compounds of the disclosure can be prepared using the knowledge of oneskilled in the art in combination with the present disclosure. Forexample, compounds of the disclosure can be prepared according to thefollowing schemes and examples.

Abbreviations

Table 1. Abbreviations and acronyms used herein include the following.

TABLE 1 Term Acronym/Abbreviation Acetonitrile ACN, MeCNtert-Butylcarbamoyl BOC Di-tert-butyl dicarbonate (Boc)₂OBenzotriazol-1-yloxytris(dimethylamino)- BOP phosphoniumhexafluorophosphate 1,1′-Carbonyldiimidazole CDI Diatomaceous EarthCelite ® 545, (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-COMU ® morpholino-carbenium hexafluorophosphate1,8-Diazabicyclo[5.4.0]undec-7-ene DBU Methylene chloride,dichloromethane DCM Diisopropyl azodiformate DIADN,N-Diisopropylethylamine DIPEA, DIEA, Hunig's baseN,N-Dimethylformamide DMF 4-Dimethylaminopyridine DMAP Dimethylsulfoxide DMSO Deutero-dimethyl sulfoxide DMSO-d₆ Diphenylphosphinoferrocene dppf Bis[(2-diphenylphosphino)phenyl] ether DPEphosDi-tert-butylphosphino ferrocene dtbpf1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EDCI, EDC, EDACElectrospray Ionisation ESI Ethyl Acetate EtOAc, or EA, or AcOEt EthanolEtOH Flash Column Chromatography FCC2-(1H-9-Azobenzotriazole-1-yl)-1,1,3,3-tetramethylaminium HATUhexafluorophosphate Acetic Acid HOAc, AcOH 1-Hydroxy-7-azabenzotriazoleHOAT, HOAt 1-Hydroxy-benzotriazole HOBt High-pressure liquidchromatography HPLC Isopropyl Alcohol IPA Deteromethanol MeOD-d₄Methanol MeOH Methanesulfonyl chloride MsCl Methyl tert-butyl ether MTBESodium methoxide NaOMe Tetrakis(triphenylphosphine)palladium(0)Pd(PPh₃)₄ Palladium(II) acetate Pd(OAc)₂[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl₂Palladium(II)bis(triphenylphosphine) dichloride, PdCl₂(PPh₃)₂bis(triphenylphosphine)palladium(II) dichloride Triphenylphosphine PPh₃Precipitate ppt p-Toluenesulfonic acid p-TsOH, PTSA(benzotriazol-1-yl-oxytripyrrolidinophosphonium PyBOPhexafluorophosphate) Bromotripyrrolidinophosphonium hexafluorophosphatePyBrOP ® Room temperature rt Supercritical Fluid Chromatography SFCThionyl chloride SOCl₂ Tetrabutylammonium fluoride TBAFtert-Butyl(chloro)dimethylsilane TBSCl Triethyl amine TEATrifluoroacetic acid TFA Trifluoroacetic anhydride TFAA TetrahydrofuranTHF Thin Layer Chromatography TLC

Preparative Examples

Exemplary compounds useful in methods of the disclosure will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples to follow.

According to SCHEME 1, a compound of formula (VI), where ring B is aC₄₋₁₀heterocycloalkyl such as azetidinyl, pyrrolidinyl, piperidinyl, andthe like; and PG is a suitable nitrogen protecting group such as BOC, iscommercially available or is synthetically accessible employingconditions known to one skilled in the art, from a compound of formula(XXV). Acylation of a heterocycloalkyl compound of formula (VI), isachieved with a suitable acylating agent such as the anhydrides andhalides of carboxylic acids such as acetic anhydride, propionicanhydride, prop-2-enoyl chloride, C₁₋₆alkyl(C═O)Cl, and the like, in thepresence of a suitable base such as TEA, DIPEA, and the like, with orwithout the presence of a reagent such as DMAP, in a suitable solventsuch as THF, DCM, and the like, at temperatures ranging from 0° C. to25° C., for a period of 2 to 6 h. Subsequent deprotection of thetert-butylcarbamate (BOC) protecting group (PG), is accomplished byusing an acid such as HCl, TFA, p-toluenesulfonic acid, in a solventsuch as MeOH, dioxane, or DCM. In a preferred embodiment, deprotectionis achieved with HCl/MeOH or TFA/DCM, to provide a compound of formula(VII).

A compound of formula (VI), where ring B is a C₅₋₆cycloalkyl, and Y isNH₂ is prepared from a compound of formula (VI), where ring B is aC₅₋₆cycloalkyl, and Y is OH under Mitsonobu conditions. In two steps,reaction of a compound of formula (VI), where Y is OH, withtriphenylphosphane, DIAD, and, phthalimide, followed by hydrazinolysiswith hydrazine hydrate in a solvent such as EtOH, provides a compound offormula (VI), where ring B is a C₅₋₆cycloalkyl, PG is BOC, and Y is NH₂.

A compound of formula (VI), where ring B is a C₅₋₆cycloalkyl, PG is BOC,and Y is CO₂H, is reacted with diphenyl phosphorazidate (DPPA),phenylmethanol, and a base such as TEA, in a solvent such as toluene, ata temperature of about 100° C., for a period of 18-24 h, to provide acompound (VI) where PG is BOC, and Y is NH—(C═O)OCH₂phenyl. Deprotectionof the CBz, under conditions known to one skilled in the art, forexample, hydrogenation using (H₂, 30 psi) using Pd(OH)₂, affords acompound of formula (VI), where PG is BOC, and Y is NH₂.

According to SCHEME 2, a synthetically accessible or commerciallyavailable compound of formula (VIII), where A is phenyl, or a sixmembered heteroaryl ring containing one or two nitrogen members, HAL isBr or F, and R^(a) is independently H, halogen, and CH₃, is reacted inan aromatic nucleophilic substitution reaction with a commerciallyavailable or synthetically accessible alcohol of formula G¹-OH (X),where G¹ is phenyl, C₃₋₆cycloalkyl, or C₁₋₆alkyl, a suitable base suchas NaH, Na₂CO₃, NaHCO₃, K₂CO₃, Cs₂CO₃, and the like, in a suitablesolvent such as DMF, DMA, THF, dioxane, and the like, to provide acompound of formula (XII), where E is O.

In an alternate method, a compound of formula (XII), where E is O, isprepared from a compound of formula (VIII), where HAL is F, and R^(a) isOH, in a coupling reaction. For example, reaction of a compound offormula (VIII) with a commercially available or synthetically accessiblearyl or heteroaryl boronic acid or ester such as phenyl boronic acid ametal catalyst such as copper (II) acetate, a base such astrimethylamine, in a solvent such as DCM, and the like, for a period ofabout 16 h, provides a compound of formula (XII) where R^(a) is F and Eis O.

A compound of formula (IX), where R^(a) is C₁₋₆alkyl, is reacted with acommercially available or synthetically accessible compound of formulaLG-G¹ (XI), where LG is a leaving group such as Cl, Br, I, ormethanesulfonate, and G¹ is C₁₋₆alkyl, C₃₋₆cycloalkyl orC₃₋₆heterocycloalkyl, a suitable base such as NaH, Na₂CO₃, NaHCO₃,K₂CO₃, Cs₂CO₃, and the like, in a suitable solvent such as DMF, DMA,THF, dioxane, and the like, to provide a compound of formula (XII),where E is O, and G¹ is C₁₋₆alkyl, C₃₋₆cycloalkyl orC₃₋₆heterocycloalkyl.

A compound of formula (XII), where ring A is pyridyl, E is N-PG, and G¹is C₁₋₆alkyl, is prepared from a compound of formula (VII), where HAL isCl, and R^(a) is C₁₋₆alkyl. For example,2-chloro-4-methyl-5-nitropyridine is reacted with an amine such aspropan-2-amine, followed by reaction with DMAP, di-tert-butyldicarbonate, in a solvent such as THF, to provide a compound of formula(XII), where ring A is pyridyl, E is N, substituted with a protectinggroup (BOC), and G¹ is C₁₋₆alkyl.

Reduction of the nitro moiety of a compound of formula (XII), where E isO or N-PG, G¹ is phenyl, C₁₋₆alkyl, C₃₋₆cycloalkyl, pyridyl, employingconditions known to one skilled in the art, for example, reduction withiron (Fe), in a solvent such as EtOH/water, in the presence of NH₄Cl orconcentrated HCl, at a temperatures ranging from 0° C. to 25° C., for aperiod of 2 to 6 h, provides the corresponding aniline of formula(XIII). Reduction of a nitro compound of formula (VII), is also achievedusing hydrogenation conditions, for example, reaction with a palladiumcatalyst such as Pd/C, Pd(OH)₂, Pt/C and the like, in a suitable solventsuch as THF, MeOH, EtOAc, or a mixture thereof, in the presence of H₂(for example at atmospheric pressure or at 30 to 50 PSI), attemperatures ranging from rt to 50° C., to provide an amine compound offormula (XIII). Reduction of a nitro compound of formula (XII), is alsoachieved employing Zn, ammonium chloride, in a suitable solvent orsolvent mixture such as acetone/water, at a temperature ranging from 0°C. to rt, for a period of about 2-6 h, to provide an amine compound offormula (XIII).

According to SCHEME 3, a compound of formula (XIV), where ring A is asuitably substituted phenyl or heteroaryl containing 1-2 nitrogenmembers, and HAL is I, Cl, or Br, and R^(a) is C₁₋₆alkyl, is reacted ina Copper-Catalyzed Cross-Coupling reaction with a compound of formulaG¹-OH, where G¹ is phenyl, or heteroaryl containing 1-2 nitrogenmembers. For example, a compound of formula (XV) such as2-chloro-4-methylpyrimidin-5-amine, is reacted with a compound offormula (X), such as phenol, a copper catalyst such as Cu, CuI, and thelike, N,N-dimethylglycine, a base such as K₂CO₃, Cs₂CO₃, and the like,in a suitable solvent such as dioxane, DMSO, and the like, at atemperature of about 90° C., for a period of 1 to 3 days, provides4-methyl-2-phenoxypyrimidin-5-amine. In an alternate method, couplingreactions are performed in the absence of a catalyst, employingmicrowave or conventional heating, with a base such as K₂CO₃, in asolvent such as DMSO.

A compound of formula (XVI) is also prepared from a compound of formula(IX) in two steps. In a first step, coupling with a compound of formula(IX), where ring A is phenyl, or a heteroaryl ring containing 1-2nitrogen members, R^(a) is C₁₋₆alkyl, is reacted with a compound offormula LG-G¹, where LG is Cl, and G¹ is C₁₋₆alkyl, phenyl, or 6membered heteroaryl ring containing 1 to 2 nitrogen members aspreviously described. In a second step, reduction of the nitro moietyemploying conditions known to one of skill in the art provides acompound of formula (XVI).

According to SCHEME 4, an aryl halide compound of formula (XIV), wherering A is phenyl, or a heteroaryl ring containing 1-2 nitrogen members,HAL is Cl, Br, and R^(a) is H or C₁₋₆alkyl, undergo a transition metalcatalyzed cross-coupling reaction such as Suziki, Negishi, and Grignardreactions. For example, reaction of a compound of formula (XIV) with acommercially available or synthetically accessible alkyl or aryl boronicacid or ester, in the presence of a suitable palladium catalyst such asPd(PPh₃)₄, Pd(OAc)₂, Pd(dppf)Cl₂, and the like, a base such as Cs₂CO₃,K₂CO₃, Na₂CO₃, and the like, in a suitable solvent such as ACN, THF,MeOH, EtOH, toluene, dioxane, water, or a mixture thereof, employingconventional or microwave heating, at temperatures ranging from 80° C.to 120° C., for a period of 12, to 24 h, to provide a compound offormula (XVII), where G¹ is C₁₋₆alkyl, or phenyl.

In a similar fashion, an aryl an aryl halide compound of formula (XIV),where ring A is phenyl, or a heteroaryl ring containing 1-2 nitrogenmembers, HAL is Cl, Br, and R^(a) is H or C₁₋₆alkyl, is reacted with aGrignard reagent such as such as isopropylmagnisium chloride, or anorganozinc reagent such as isobutylzinc(II) bromide, cyclobutylzinc(II)bromide, and the like, in the presence of a palladium catalyst such asPd(dppf)Cl₂.DCM, Pd(dppf)₂Cl₂, and the like, in a suitable solvent suchTHF, at temperatures ranging from −78° C. to the reflux temperature ofthe solvent, to provide a compound of formula (XVII), where G¹ isC₁₋₆alkyl.

According to SCHEME 5, aryl halides of formula (XVIII), where HAL is I,Cl or Br, undergo a palladium catalyzed arylation with a compound offormula (XVI) or (XVII), where G¹ is phenyl, and C₃₋₆cycloalkyl, R^(a)is H or C₁₋₆alkyl, in the presence of a palladium catalyst such asPd(OAc)₂, Pd₂(dba)₃, and the like, a ligand such as Xantphos, S-Phos,BINAP, DPEPhos, a suitable base such as NaOtBu, Cs₂CO₃, K₃PO₄, and thelike, in a suitable solvent such as ACN, THF, toluene, dioxane, and thelike, employing conventional or microwave heating, at temperaturesranging from 60 to 120° C., to provide a compound of formula (XIX),where E is a bond, or O.

According to SCHEME 6, a nitrile compound of formula (XIX) is reacted ina nucleophilic aromatic substitution reaction with ethyl thioacetate,under basic conditions, followed by ring closure, to afford athienopyridine-carboxylate compound of formula (XX). A compound offormula (XXI) is prepared in two steps from a compound of formula (XX).In a first step, reaction of a compound of formula (XX) with CDI; insuitable solvent such as 1, dioxane, and the like; at refluxtemperature; for a period of 12-24 h. In a second step, hydrolysis ofthe ester moiety, with a suitable base such as NaOH, LiOH, and the like,in a solvent such as MeOH, and the like, at temperatures ranging from rtto 50° C., for a period of 12 to 24 h, affords an acid compound offormula (XXI).

According to SCHEME 7, an acid compound of formula (XXI), as describedabove, is first converted to an acid chloride compound of formula(XXII). For example, a compound of formula (XXI) is treated with achlorinating agent such as thionyl chloride and the like; in a solventsuch as toluene, and the like, to form a compound of formula (XXII).

Coupling reactions are achieved by conventional amide bond formingtechniques which are well known to one of skill in the art as depictedin SCHEME 5. For example, an acyl halide (eg, chloride) compound offormula (XXI), is reacted with a suitably substituted commerciallyavailable or synthetically accessible amine of formula (XXV), (VI), or(VII) in the presence of an excess of a tertiary amine, such as TEA,pyridine, and the like, optionally in the presence of a suitablecatalyst such as DMAP, in a suitable solvent such as DCM or THF, at atemperature ranging from room temperature to the reflux temperature ofthe solvent, to provide a compound of Formula (I′). A variety of otheramino acid coupling methodologies are used to couple the compounds offormula (XXI). Reaction of a suitably substituted commercially availableor synthetically accessible amine of formula (XXV), (VI), or (VII); witha suitably substituted acid of formula (XXI) under amide bond formingconditions provides a compound of Formula (I′). In a preferredembodiment, a compound of formula (XXV), (VI), or (VII), either as afree base or as an acid salt, is reacted with an acid compound offormula (XXI), in the presence of a dehydrating agent such as HOBt/EDAC,HATU, HOAT, T3P®, and the like; a suitably selected base such as DIPEA,TEA, and the like; in an organic solvent or mixture thereof such astoluene, acetonitrile, ethyl acetate, DMF, THF, methylene chloride, andthe like; to afford a compound of Formula (I′). In a particularlypreferred embodiment, the dehydrating agent is HATU and the base is TEAor DIPEA. In cases where the amine compound of formula (XXV), (VI), or(VII) has a tert-butylcarbamate (BOC) protecting group (PG), removal ofthe tert-butylcarbamate (BOC) protecting group (PG), is accomplished byusing an acid such as HCl, TFA, p-toluenesulfonic acid, in a solventsuch as MeOH, dioxane, or DCM. In a preferred embodiment, deprotectionis achieved with HCl/MeOH or TFA/DCM.

A compound of Formula (I′), where R² is a suitably substitutedC₄₋₁₀heterocycloalkyl, is reacted under reductive amination conditionswith an suitable aldehyde such as formaldehyde, paraformaldehyde, areducing agent such as NaBH₄, NaBH(OAc)₃, and the like, in a suitablesolvent such as DCM, MeOH, THF, and the like, to afford a compound ofFormula (I′), where R² is C₄₋₁₀heterocycloalkyl substituted with CH₃.

A compound of Formula (I′), where R² is C₄₋₁₀heterocycloalkyl, isreacted with acylating agent such as the anhydrides and halides ofcarboxylic acids such as acetic anhydride, prop-2-enoyl prop-2-enoate,propionic anhydride, C₁₋₆alkyl(C═O)Cl, and the like, under conditionspreviously described, to provide a compound of Formula (I′), where R² isC₄₋₁₀heterocycloalkyl substituted with (C═O)C₁₋₃alkyl, and(C═O)C₁₋₃alkenyl.

A compound of Formula (I′), where R² is C₄₋₁₀heterocycloalkyl is reactedwith a suitable acid of such as CO₂H-C₁₋₆alkyl-N(R⁶R⁷),2-(dimethylamino)acetic acid, cyanoacetic acid, Boc-sarcosine,2-(tert-butoxycarbonylamino)acetic acid,(E)-4-(dimethylamino)but-2-enoic acid, acrylic acid, and the like, underamide bond forming conditions previously described conditions to providea compound of Formula (I′). A deprotection step, employing conditionspreviously described is employed where applicable.

According to SCHEME 8, a nitrile compound of formula (XIX) is reacted ina nucleophilic aromatic substitution reaction withtert-butyl-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate, in asealed vessel under high heat such as 150° C. for a period of time form15 min to 1 hr, followed by ring closure, to afford athienopyridine-carboxamide compound of formula (XXIII). A compound ofFormula (I′) is prepared in two steps from a compound of formula(XXIII). In a first step, reaction of a compound of formula (XXIII) withCDI; in suitable solvent such as dioxane, and the like; at refluxtemperature; for a period of 12-24 h. In a second step, deprotection ofthe amine moiety, with a suitable acid such as HCl or TFA, and the like,in a solvent such as dioxane, and the like, at temperatures ranging fromrt to 40° C., for a period of 30 min to 24 h, affords an amine compoundof Formula (I′).

Compounds of Formula (I′) may be converted to their corresponding saltsusing methods known to one of ordinary skill in the art. For example, anamine of Formula (I′) is treated with trifluoroacetic acid, HCl, orcitric acid in a solvent such as Et₂O, CH₂Cl₂, THF, MeOH, chloroform, orisopropanol to provide the corresponding salt form. Alternately,trifluoroacetic acid or formic acid salts are obtained as a result ofreverse phase HPLC purification conditions. Cyrstalline forms ofpharmaceutically acceptable salts of compounds of Formula (I′) may beobtained in crystalline form by recrystallization from polar solvents(including mixtures of polar solvents and aqueous mixtures of polarsolvents) or from non-polar solvents (including mixtures of non-polarsolvents).

Where the compounds according to this disclosure have at least onechiral center, they may accordingly exist as enantiomers. Where thecompounds possess two or more chiral centers, they may additionallyexist as diastereomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentdisclosure.

Compounds prepared according to the schemes described above may beobtained as single forms, such as single enantiomers, by form-specificsynthesis, or by resolution. Compounds prepared according to the schemesabove may alternately be obtained as mixtures of various forms, such asracemic (1:1) or non-racemic (not 1:1) mixtures. Where racemic andnon-racemic mixtures of enantiomers are obtained, single enantiomers maybe isolated using conventional separation methods known to one ofordinary skill in the art, such as chiral chromatography,recrystallization, diastereomeric salt formation, derivatization intodiastereomeric adducts, biotransformation, or enzymatic transformation.Where regioisomeric or diastereomeric mixtures are obtained, asapplicable, single isomers may be separated using conventional methodssuch as chromatography or crystallization.

The following specific examples are provided to further illustrate thedisclosure and various preferred embodiments.

Examples

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atrt (rt) under a nitrogen atmosphere. Where solutions were “dried,” theywere generally dried over a drying agent such as Na₂SO₄ or MgSO₄. Wheremixtures, solutions, and extracts were “concentrated”, they weretypically concentrated on a rotary evaporator under reduced pressure.Reactions under microwave irradiation conditions were carried out in aBiotage Initiator or CEM (Microwave Reactor) Discover instrument.

Normal-phase silica gel chromatography (FCC) was performed on silica gel(SiO₂) using prepacked cartridges.

Preparative reverse-phase high performance liquid chromatography (RPHPLC) was performed on either: An Agilent HPLC with an Xterra Prep RP18column (5 μM, 30×100 or 50×150 mm) or an XBridge C18 OBD column (5 μM,30×100 or 50×150 mm), and a mobile phase of 5% ACN in 20 mM NH₄OH washeld for 2 min, then a gradient of 5-99% ACN over 15 min, then held at99% ACN for 5 min, with a flow rate of 40 or 80 mL/min.

or

A Shimadzu LC-8A Series HPLC with an Inertsil ODS-3 column (3 m, 30×100mm, T=45° C.), mobile phase of 5% ACN in H₂O (both with 0.05% TFA) washeld for 1 min, then a gradient of 5-99% ACN over 6 min, then held at99% ACN for 3 min, with a flow rate of 80 mL/min.

or

A Shimadzu LC-8A Series HPLC with an XBridge C18 OBD column (5 μm,50×100 mm), mobile phase of 5% ACN in H₂O (both with 0.05% TFA) was heldfor 1 min, then a gradient of 5-99% ACN over 14 min, then held at 99%ACN for 10 min, with a flow rate of 80 mL/min.

or

A Gilson HPLC with an XBridge C18 column (5m, 100×50 mm), mobile phaseof 5-99% ACN in 20 mM NH₄OH over 10 min and then hold at 99 ACN for 2min, at a flow rate of 80 mL/min.

Quality control testing includes identity, chemical, and radiochemicalpurity by HPLC using an XBridge C18 (5 m, 4.6×250 mm) column eluted witha mixture of methanol/ammonium acetate 5 mM, 65/35, v/v at a flow rateof 1 mL/min equipped with serial UV (280 nm) and gamma detection.

Preparative supercritical fluid high performance liquid chromatography(SFC) was performed either on a Jasco preparative SFC system, an APS1010 system from Berger instruments, or a SFC-PICLAB-PREP 200 (PICSOLUTION, Avignon, France). The separations were conducted at 100-150bar with a flow rate ranging from 40-60 mL/min. The column was heated to35-40° C.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in positive mode unless otherwiseindicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. Definitions for multiplicity are as follows:s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad. Itwill be understood that for compounds comprising an exchangeable proton,said proton may or may not be visible on an NMR spectrum depending onthe choice of solvent used for running the NMR spectrum and theconcentration of the compound in the solution.

Chemical names were generated using ChemDraw Ultra 12.0, ChemDraw Ultra14.0 (CambridgeSoft Corp., Cambridge, Mass.) or ACD/Name Version 10.01(Advanced Chemistry).

Compounds designated as R* or S* are enantiopure compounds where theabsolute configuration was not determined.

Chiral Resolution Method A.

The atropisomers were chromatographed to isolate the two separateatropisomers, with the respective single atropisomers arbitrarilylabeled as *S or *R to indicate that the compound is a singleatropisomer of unknown absolute configuration. In cases for whichabsolute configuration of a single atropisomeric compound wasdetermined, the atropisomers are named as either S or R throughout (withS corresponding to the alternate designations aS, S_(a), or P; and withR corresponding to the alternate designations aR, R_(a), or M). Thepurification was performed on a chiral SFC column (Stationary phase:Whelk O1 (S,S), 5 μm, 250×21.1 mm column. The mobile phase was: 40% CO₂,60% MeOH (0.2% formic acid).

Intermediate 1: tert-Butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate

A mixture of (3R,5S)-tert-butyl3-azido-5-hydroxypiperidine-1-carboxylate (Intermediate 2, Step I) (1.5g, 6.19 mmol) in DCM at −78° C. was reacted by slow addition of DAST(1.2 g, 7.43 mmol). The reaction solution was stirred at −78° C. for 2 hand at rt for 16 h. The reaction was quenched by the addition ofsaturated aqueous NaHCO₃. The organic layer was separated, washed withaqueous NaHCO₃ solution, water, dried over anhydrous Na₂SO₄, andconcentrated to dryness. The residue was reduced using conditionsanalogous to step J of Intermediate 2 to yield the title compound (660mg, 44%) MS (ESI): mass calcd. for C₁₀H₁₉FN₂O₂, 218.1; m/z found, 219.1[M+H]⁺.

Intermediate 2: tert-Butyl (3R,5S)-3-amino-5-hydroxypiperidine-1-carboxylate

Step A: (2R,4S)-Methyl 1-benzyl-4-hydroxypyrrolidine-2-carboxylate

To a round bottom flask were added methyl(2R,4S)-4-hydroxypyrrolidine-2-carboxylate (12 g, 83 mmol) and DCM (150mL). To the reaction mixture were added triethylamine (33.3 g, 330 mmol)and benzylbromide (17 g, 99 mmol) at rt, and then was heated to refluxfor 16 h. The reaction mixture was washed with saturated NaHCO₃,extracted with EtOAc, and dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by flash columnchromatography to yield the title compound (9.2 g, 42%) as a colorlessoil. MS (ESI): mass calcd. for C₁₀H₂₀N₂O₃, 216.1; m/z found, 217.1[M+H]⁺.

Step B: (2R,4S)-Methyl1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylate

To a round bottom flask were added (2R,4S)-methyl1-benzyl-4-hydroxypyrrolidine-2-carboxylate (9.2 g, 39 mmol), DCM (200mL), triethylamine (7.90 g, 7.82 mmol), TBSCl (7.07 g, 47.0 mmol), andDMAP (48 mg, 0.39 mmol) at rt. The reaction mixture was heated to refluxfor 16 h, cooled to rt, washed with saturated NaHCO₃, extracted withEtOAc, dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was purified by flash column chromatography toyield the title compound (13 g, 40%) as a colorless oil. MS (ESI): masscalcd. for C₁₉H₃₁NO₃Si, 349.2; m/z found, 350.1 [M+H]+.

Step C:((2R,4S)-1-Benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methanol

To a round bottom flask were added (2R,4S)-methyl1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylate (13g, 37 mmol), THF (50 mL), and LiBH₄ (2.0 g, 93 mmol) at 0° C. Thereaction was allowed to warm to rt and was stirred for an additional 16hrs at rt. The reaction mixture was washed with saturated NaHCO₃,extracted with EtOAc, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by flash columnchromatography to obtain the title compound (6 g, 50%) as a yellow oil.MS (ESI): mass calcd. for C₁₈H₃₁NO₂Si, 321.2; m/z found, 322.1 [M+H]⁺.

Step D: (3S,5S)-1-Benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-ol

To a round bottom flask were added((2R,4S)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methanol(6.0 g, 19 mmol), THF (20 mL), and triethylamine (5.7 mL, 28 mmol). Thereaction mixture was cooled to 0° C. and to this was added TFAA (5.9 g,28 mmol). The reaction mixture was allowed to warm to rt and was reactedat rt for 16 h. The reaction mixture was washed with saturated NaHCO₃,extracted with EtOAc, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by flash columnchromatography to yield the title compound (3 g, 50%) as a yellow oil.MS (ESI): mass calcd. for C₁₈H₃₁NO₂Si, 321.2.1; m/z found, 322.0 [M+H]⁺.

Step E: (3S,5S)-5-((tert-Butyldimethylsilyl)oxy)piperidin-3-ol

To a round bottom flask were added(3S,5S)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-ol (3.0 g,9.3 mmol), EtOH (20 mL), and Pd/C (10% on activated carbon, 600 mg). Tothe reaction mixture was added H₂ and was reacted at rt for 16 h. Thereaction mixture was filtered and concentrated to dryness to yield thetitle compound (2.4 g, quantitative) as a yellow oil. MS (ESI): masscalcd. for C₁₁H₂₅NO₂Si, 231.2; m/z found, 232.2 [M+H]⁺.

Step F: tert-Butyl(3S,5S)-3-[tert-butyl(dimethyl)silyl]ox-5-hydroxypiperidine-1-carboxylate

To a round bottom flask were added(3S,5S)-5-((tert-butyldimethylsilyl)oxy)piperidin-3-ol (2.4 g, 10 mmol),DCM (20 mL), triethylamine (2.1 g, 21 mmol), and (Boc)₂O (2.7 g, 12mmol) at 0° C. and was reacted at rt for 1 h. The reaction was quenchedwith saturated NaHCO₃, extracted with EtOAc, dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby flash column chromatography to yield the title compound (3.3 g, 96%)as a yellow oil. MS (ESI): mass calcd. for C₁₆H₃₃NO₄Si, 331.2; m/zfound, 332.1 [M+H]⁺.

Step G: tert-Butyl(3S,5S)-3-[tert-butyl(dimethyl)silyl]oxy-5-methylsulfonyloxypiperidine-1-carboxylate

To a round bottom flask were added tert-butyl(3S,5S)-3-[tert-butyl(dimethyl)silyl]oxy-5-hydroxypiperidine-1-carboxylate(3.3 g, 10 mmol), DCM (20 mL), triethylamine (3 g, 29 mmol), and MsCl(1.7 g, 14.5 mmol) at 0° C. The reaction mixture was allowed to warm tort and was reacted at rt for 2 h. The reaction was quenched withsaturated NaHCO₃, extracted with EtOAc, dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness to yield the title compound (4 g,98%) as a yellow oil. MS (ESI): mass calcd. for C₁₇H₃₅NO₆SSi, 409.2; m/zfound, 410.1 [M+H]⁺.

Step H: (3R,5S)-tert-Butyl3-azido-5-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate

To a round bottom flask were added tert-butyl(3S,5S)-3-[tert-butyl(dimethyl)silyl]oxy-5-methylsulfonyloxypiperidine-1-carboxylate(3.6 g, 8.8 mmol), DMF (20 mL), and NaN₃ (1.7 g, 26 mmol) at rt. Thereaction was reacted at 70° C. for 72 h. The reaction was quenched withsaturated NaHCO₃, extracted with EtOAc, dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness. The residue was purified by flashcolumn chromatography to yield the title compound (3.0 g, 96%) as ayellow oil.

Step I: (3R,5S)-tert-Butyl 3-azido-5-hydroxypiperidine-1-carboxylate

To a round bottom flask were added (3R,5S)-tert-butyl3-azido-5-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (3.0 g,8.4 mmol), THF (10 mL), and TBAF (1 M solution, 10 mL, 10 mmol) insequence at 0° C. The reaction solution was warmed to rt and reacted atrt for 16 h. The reaction was quenched by the addition of water,extracted with EtOAc, dried over anhydrous Na₂SO₄, filtered,concentrated to dryness, and purified by flash column chromatography toyield the title compound (1.4 g, 69%) as a yellow oil. Mass calcd. forC₁₀H₁₈N₄O₃, 242.1. ¹H NMR (400 MHz, CDCl₃): δ 9.89-3.62 (m, 3H),3.58-3.31 (m, 1H), 3.08-3.88 (m, 2H), 2.25-2.10 (m, 1H), 1.64-1.51 (m,1H), 1.42 (s, 9H).

Step J: (3R,5S)-tert-Butyl 3-amino-5-hydroxypiperidine-1-carboxylate

A mixture of (3R,5S)-tert-butyl3-azido-5-hydroxypiperidine-1-carboxylate (500 mg, 2.06 mmol), Pd/C (10%on activated carbon, 200 mg), and MeOH (5 mL) were reacted at rt underH₂ for 16 h. The reaction mixture was filtered and concentrated todryness. No further purification (407 mg, 91% yield). MS (ESI): masscalcd. for C₁₀H₂₀N₂O₃, 216.1; m/z found, 217.0 [M+H]⁺.

Intermediate 3: tert-Butyl (3R,5S)-3-amino-5-fluoropiperidine-1-carboxylate

Step A: (3R,5R)-tert-Butyl 3-azido-5-hydroxypiperidine-1-carboxylate

The title compound was prepared using analogous conditions described insteps A-I of Intermediate 2, and using methyl(2R,4R)-4-hydroxypyrrolidine-2-carboxylate in place of methyl(2R,4S)-4-hydroxypyrrolidine-2-carboxylate in step A.

Step B: (3R,5S)-tert-Butyl 3-azido-5-fluoropiperidine-1-carboxylate

To a solution of (3R,5R)-tert-butyl3-azido-5-hydroxypiperidine-1-carboxylate (1.5 g, 6.2 mmol) in dry DCM(50 mL) at −78° C. was added DAST (1.2 g, 7.4 mmol) slowly. The reactionsolution was stirred at −78° C. for 2 h and at rt for 16 h. The reactionwas quenched by addition of saturated aqueous NaHCO₃ solution and theorganic layer was separated and washed with aqueous NaHCO₃ solution andwater, dried over anhydrous Na₂SO₄, and concentrated to dryness. Theresidue was purified by flash column chromatography to yield the titlecompound as a colorless oil (660 mg, 44% yield). C₁₀H₁₇FN₄O₂. ¹H NMR(400 MHz, CDCl₃): δ 4.80 (d, J=46.5 Hz, 1H), 4.32-3.95 (m, 1H),3.95-3.71 (m, 2H), 3.39-2.63 (m, 2H), 2.41-2.12 (m, 1H), 1.86-1.57 (m,1H), 1.46 (s, 9H).

Step C: (3R,5S)-tert-Butyl 3-amino-5-fluoropiperidine-1-carboxylate

To a solution of (3R,5S)-tert-butyl3-azido-5-fluoropiperidine-1-carboxylate (660 mg, 2.7 mmol) in MeOH (60mL) was added Pd/C (10% Pd on C, 130 mg) and the mixture was stirred atrt under H₂ overnight, then filtered and concentrated to dryness toyield the title compound as a yellow oil (450 mg, 76% yield). MS (ESI):mass calcd. for C₁₀H₁₉FN₂O₂, 218.1; m/z found, 219.1 [M+H]⁺.

Intermediate 4: tert-Butyl(3R,5R)-3-amino-5-hydroxypiperidine-1-carboxylate

The title compound was prepared using conditions analogous toIntermediate 2, steps A-J, and using(2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid in place of methyl(2R,4S)-4-hydroxypyrrolidine-2-carboxylate in step A. MS (ESI): masscalcd. for C₁₀H₂₀N₂O₃, 216.1; m/z found, 217.1 [M+H]⁺.

Intermediate 5: 1-[(3R)-3-Aminopyrrolidin-1-yl]prop-2-en-1-one

A solution of tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (5.0 g, 27mmol) and DIEA (4.156 g, 32.21 mmol) in DCM (60 mL) was cooled to 0° C.and prop-2-enoyl chloride (2.43 g, 26.8 mmol) was added portion wise andstirred at rt for 1 h. The mixture was concentrated to dryness andpurified by flash column chromatography to get pure product, which wasdissolved in concentrated HCl (30 mL) and MeOH (30 mL) and was stirredat rt for 0.5 h. The mixture was concentrated to dryness to give thetitle compound as a yellow oil (3.98 g, 83.9% yield). MS (ESI): masscalcd. for C₇H₁₂N₂O, 140.1; m/z found, 141.1 [M+H]⁺.

Intermediate 6: tert-Butyl(3R,5R)-3-amino-5-methoxypiperidine-1-carboxylate

The title compound was prepared using Method 2, steps A-J, and using(1R,3S)-3-hydroxycyclopentane carboxylic acid in place of methyl(2R,4S)-4-hydroxypyrrolidine-2-carboxylate in step A, and at step J,first the methyl ester is formed, followed by reduction to obtaintert-butyl (3R,5R)-3-amino-5-hydroxypiperidine-1-carboxylate. MS (ESI):mass calcd. for C₁₀H₂₀N₂O₃: 216.1; m/z found, 217.1 [M+H]⁺.

Intermediate 7: 4-Isopropyl-2-methyl-aniline

To a solution of 4-iodo-2-methyl-aniline (4.0 g, 17 mmol) andPd(dppf)₂Cl₂ (140 mg, 0.17 mmol) in THF (50 mL) was addedisopropylmagnisium chloride (25.5 mL, 51.0 mmol) at −78° C. and wasreacted at reflux for 4 h. The reaction was quenched with a saturatedsolution of NH₄Cl, extracted with EtOAc, dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness. The residue was purified by flashcolumn chromatography to give the title compound as a brown solid (320mg, 12%). MS (ESI): mass calcd. for C₁₀H₁₅N, 149.1; m/z found, 150.0[M+H]⁺.

Intermediate 8: Benzofuran-7-ol

Step A: 7-Methoxybenzofuran

To a round bottom flask were added 7-methoxy-2-benzofuran-2-carboxylicacid (5.0 g, 0.026 mol), copper (0.2 g, 3 mmol), and quinoline (30 mL).The reaction mixture was heated at reflux for 2 h. The mixture wasfiltered through Celite and washed with EtOAc, concentrated to dryness,and purified by flash column chromatography to yield the title compound(2.45 g, 64% yield) as a yellow oil. MS (ESI): mass calcd. for C₉H₈O₂,148.1; m/z found, 149.0 [M+H]⁺.

Step B: Benzofuran-7-ol

To a round bottom flask containing 7-methoxybenzofuran (2.45 g, 16.5mmol) and anhydrous DCM (25 mL) was carefully added a solution of borontribromide in DCM (1 M, 33 mL) at 0° C. The reaction was allowed to warmto rt and stir at rt for 4 h. The reaction was quenched with water (20mL), extracted with Et₂O, concentrated to dryness, and purified by flashcolumn chromatography to yield the title compound (1.23 g, 55% yield) asa light-brown oil. MS (ESI): mass calcd. for C₈H₆O₂, 134.0.1; m/z found,135.1 [M+H]⁺.

Intermediate 9: 2-Fluoro-6-methyl-4-phenoxyaniline

Step A: 4-Bromo-2-fluoro-6-methylaniline

To a round bottom flask were added 2-fluoro-6-methylaniline (7 g, 56mmol) and anhydrous DMF (100 mL). The reaction mixture was cooled in anice bath, placed under a nitrogen atmosphere, and treated withN-bromosuccinimide (10 g, 56 mmol). The reaction was allowed to warm tort and was stirred at rt for 10 min. The reaction mixture was pouredinto a water solution of diluted brine and extracted with EtOAc. Thecombined organic extracts were washed with diluted brine (3×), driedover anhydrous MgSO₄, filtered through a pad of silica, and concentratedto dryness. The residue was purified by flash column chromatography toyield the title compound (6.84 g, 60% yield) as a yellow foam. MS (ESI):mass calcd. for C₇H₇BrFN, 203.0; m/z found, 204 [M+H]⁺.

Step B: 2-Fluoro-6-methyl-4-phenoxyaniline

A mixture of 4-Bromo-2-fluoro-6-methylaniline (4.73 g, 23 mmol), phenol(4.4 g, 48 mmol), 1-Butylimidazole (1.4 g, 11 mmol), CuCl (230 mg, 2.3mmol) and K₂CO₃ (6.5 g, 47 mmol) was degassed and heated at 120° C.overnight. The mixture was cooled to room temperature, The mixture wasconcentrated and purified by ISCO using MeOH/H₂O as eluent to get thetitle compound as brown oil (2.23 g, 44%). MS (ESI): mass calcd. forC₁₃H₁₂FNO, 217.1; m/z found, 218 [M+H]⁺.

Intermediate 10: (E)-4-[tert-Butoxycarbonyl(methyl)amino]but-2-enoicacid

Step A: Methyl (E)-4-(methylamino)but-2-enoate

To a solution of methyl (E)-4-bromobut-2-enoate (1.79 g, 10 mmol) in THF(3 mL) was added methylamine (0.776 g, 25.0 mmol) at −20° C. over 30 minand then stirred at −5° C. for 2 h, filtered, and washed with THF. Thefiltrate was concentrated to dryness to give the title compound as abrown oil (0.96 g, 74%), which was used in the next step directly.

Step B: Methyl (E)-4-[tert-butoxycarbonyl(methyl)amino]but-2-enoate

To a solution of methyl (E)-4-(methylamino)but-2-enoate (0.96 g, 7.4mmol) and Na₂CO₃ (1.58 g, 14.9 mmol) in THF (20 mL) and H₂O (20 mL) wasadded Boc₂O (3.24 g, 14.9 mmol) and the mixture was stirred at 25° C.for 3 h. The mixture was diluted with DCM, washed with brine severaltimes, dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was purified by flash column chromatography to givethe title compound as yellow liquid (0.68 g, 40% yield).

Step C: (E)-4-[tert-Butoxycarbonyl(methyl)amino]but-2-enoic acid

To a solution of methyl(E)-4-[tert-butoxycarbonyl(methyl)amino]but-2-enoate (0.68 g, 3.0 mmol)in THF (15 mL) and water (15 mL) was added LiOH.H₂O (0.498 g, 11.9 mmol)and the mixture was stirred at rt for 12 h. The pH of the mixture wasadjusted to about 2, extracted with EtOAc, dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness to give the title compound aslight yellow liquid (0.41 g, 64% yield), which was used in the next stepdirectly. MS (ESI): mass calcd. for C₁₁H₁₉NO₄, 229.1; m/z found, 130.0[M-Boc+H]⁺.

Intermediate 11: tert-Butyl(3S,4R)-3-amino-4-methoxypyrrolidine-1-carboxylate

A mixture of tert-butyl(3S,4R)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate (500 mg, 2.47 mmol),phthalic anhydride (439 mg, 2.97 mmol), triethylamine (500 mg, 4.94mmol), and DMAP (60 mg, 0.49 mmol) in THF (20 mL) was stirred at refluxovernight. The reaction mixture was concentrated to dryness and theresidue was purified by flash column chromatography to yield theintermediate as a white solid. This material was reacted with Ag₂O(1.142 g, 4.944 mmol) in MeI (10 mL) was stirred at reflux overnight.The reaction mixture was concentrated to dryness and the residue waspurified by flash column chromatography to give the intermediate as awhite solid. A solution of this material and NH₂NH₂.H₂O (1 mL, 85%) inEtOH (5 mL) was stirred at reflux for 2 h. The solid was filtered offand the solvent was removed to give the title compound as an oil whichwas used without further purification in the next reaction.

Intermediate 12: (E)-4-(tert-Butoxycarbonylamino)but-2-enoic acid

Step A: (E)-4-Aminobut-2-enoic acid

To a round bottom flask were added (E)-4-bromobut-2-enoic acid (1 g, 6mmol) and aqueous ammonia (10 mL) and was stirred at rt for 7 h. Themixture was concentrated to dryness to yield the title compound (0.61 g,100%), which was used in the next step without purification.

Step B: (E)-4-(tert-Butoxycarbonylamino)but-2-enoic acid

To a round bottom flask containing a solution of (E)-4-aminobut-2-enoicacid (0.61 g, 6 mmol), Na₂CO₃ (1.3 g, 12 mmol), THF (15 mL), and H₂O (15mL) was added Boc₂O (2.6 g, 12 mmol). The reaction mixture was stirredat 25° C. for 15 h. Then the mixture was extracted with EtOAc and the pHof the aqueous layer was adjusted to 2 with 1 M HCl. The acidic aqueouslayer was extracted with EtOAc, washed with brine (3×), dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness to yield thetitle compound (0.24 g, 20% yield) as a white solid. MS (ESI): masscalcd. for C₉H₁₅NO₄; 201.1; m/z found, 102 [M-Boc+H]⁺.

Intermediate 13: (E)-4-Hydroxybut-2-enoic acid

Step A: Ethyl (E)-4-bromobut-2-enoate

To a round bottom flask containing ethyl (2E)-but-2-enoate (10.9 g, 87.6mmol) and CCl₄ (100 mL) were added NBS (17 g, 96 mmol) and AIBN (4.3 g,26 mmol). The reaction mixture was stirred at 80° C. for 12 h. Thereaction mixture was diluted with DCM and extracted with saturatedNaHCO₃, water, and brine. The organic layer was dried over anhydrousNa₂SO₄ and evaporated to dryness to yield the title compound (7.5 g, 44%yield) as an oil.

Step B: (E)-4-Hydroxybut-2-enoic acid

To a round bottom flask were added ethyl (E)-4-bromobut-2-enoate (2 g,10 mmol), KOH (1.2 g, 21 mmol), and water (10 mL). The reaction mixturewas stirred at 100° C. for 2 h, then acidified with 1 M HCl, andextracted with EtOAc (3×). The combined organic layers were washed withbrine, dried over anhydrous MgSO₄, and concentrated to dryness to yieldthe title compound (560 mg, 53% yield) as a brown oil.

Intermediate 14:2-Chloro-4-(4-hydroxy-2-methylanilino)pyridine-3-carbonitrile

Step A: 2-Chloro-4-(4-methoxy-2-methylanilino)pyridine-3-carbonitrile

To a round bottom flask were added2-chloro-4-iodopyridine-3-carbonitrile (1.7 g, 6.4 mmol),4-methoxy-2-methylaniline (880 mg, 6.4 mmol), DPEPhos[bis(2-diphenylphosphinophenyl)ether] (690 mg, 1.3 mmol), palladium(II)acetate (145 mg, 0.646 mmol), K₃PO₄ (3.7 g, 0.017 mmol), and dioxane (15mL). The reaction mixture was degassed and heated at 120° C. overnight.The mixture was cooled to rt, concentrated to dryness, and purified byflash column chromatography to yield the title compound (1.1 g, 63%yield) as a brown solid. MS (ESI): mass calcd. for C₁₄H₁₂ClN₃O, 273.1;m/z found, 274 [M+H]⁺.

Step B: 2-Chloro-4-(4-hydroxy-2-methylanilino)pyridine-3-carbonitrile

To a round bottom flask containing a solution of2-chloro-4-(4-methoxy-2-methylanilino)pyridine-3-carbonitrile (1.1 g, 4mmol) in anhydrous DCM (15 mL) was carefully added a solution of borontribromide in DCM (1 M, 4 mL, 4 mmol) at 0° C. The reaction mixture wasallowed to stir at rt for 4 h. The reaction was quenched with water (20mL), extracted with ethyl ether, and concentrated to dryness. Theresidue was purified by flash column chromatography to yield the titlecompound (900 mg, 86% yield) as a yellow solid. MS (ESI): mass calcd.for C₁₃H₁₀ClN₃O, 259.1; m/z found, 260.0 [M+H]⁺.

Intermediate 15: 1-[(3R)-3-Amino-1-piperidyl]prop-2-en-1-one

Step A: (R)-tert-Butyl (1-acryloylpiperidin-3-yl)carbamate

To a solution of tert-butyl N-[(3R)-3-piperidyl]carbamate (2 g, 10 mmol)in DCM (30 mL) was added triethylamine (5 g, 50 mmol) and the reactionmixture was cooled to 0° C. Prop-2-enoyl chloride (2.7 g, 30 mmol) wasadded slowly and was stirred overnight at rt. The reaction was extractedwith H₂O and DCM, the organic layer was washed with brine, dried overanhydrous Na₂SO₄, and concentrated to dryness. The crude product wasused crude in the next step without further purification.

Step B: 1-[(3R)-3-Amino-1-piperidyl]prop-2-en-1-one

(R)-tert-Butyl (1-acryloylpiperidin-3-yl)carbamate (from Step A) wasdissolved in MeOH and concentrated to dryness. Concentrated aqueous HClwas added, and the mixture was stirred for 2 h at rt. The reactionmixture was concentrated to dryness and the residue was used directly inthe next step. MS (ESI): mass calcd. for C₈H₁₄N₂O, 154.1; m/z found,155.1 [M+H]⁺.

Intermediate 16:5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using Method 1, steps A-F in Example 1(including Chiral Resolution Step A to obtain the *S atropisomer). MS(ESI): mass calcd. for C₂₂H₁₅N₃O₄S, 417.1; m/z found, 418.2 [M+H]⁺.

Intermediate 17: (E)-2-Cyano-3-cyclopropylprop-2-enoic acid

A solution of cyanoacetic acid (1.34 g, 15.7 mmol),cyclopropanecarboxaldehyde (1.0 mL, 13 mmol), NH₄OAc (101 mg, 1.31mmol), and HOAc (10 mL) in a 50 mL round bottom flask fitted with a stirbar under N₂ was warmed in a sand bath set at 110° C. The reaction wasrun until LCMS and TLC showed the reaction had gone to completion. Thereaction mixture was concentrated to dryness and water (20 mL) was addedto the white solid. This mixture was concentrated dryness and repeatedone time more. Water was added and the precipitate was filtered off toyield the title compound as a white solid (1.3 g, 72% yield). MS (ESI):mass calcd. for C₇H₇NO₂, 137.0; m/z found, 138.0 [M+H]⁺.

Intermediate 18:(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-Bromo-3-fluoro-1-nitro-4-phenoxybenzene

To a mixture of a 2-bromo-3,4-difluoro-1-nitrobenzene (15.8 g, 66.4mmol) and potassium carbonate (18.3 g, 132.8 mmol) in DMF (50 mL) wasadded phenol (6.25 g, 66.4 mmol) followed by stirring at 80° C.overnight. The title compound was collected by adding water to thereaction mixture and filtering to isolate a yellow solid (18 g, 87%).

Step B: 2-Fluoro-3-methyl-4-nitro-1-phenoxybenzene

Dimethylzinc as a 2 M solution in toluene (80.1 mL, 96.1 mmol) wasslowly added to a mixture of 2-bromo-3-fluoro-1-nitro-4-phenoxybenzene(10 g, 32.0 mmol) andpalladium-(diphenylphosphineoferrocenyl)-dichloride-methylene dichloridecomplex (1.33 g, 1.60 mmol) in dioxane (200 mL) at 40° C. The mixturewas stirred at 55° C. for 2 hours. After cooling to room temperature,methanol was slowly added followed by a saturated solution of ammoniumchloride. The resulting mixture was extracted into ethyl acetate. Theorganic phase was washed with brine, dried over anhydrous sodiumsulphate, filtered and concentrated under reduced pressure. The crudeoil was purified by flash chromatography on silica gel (PE/ethylacetate, 9/1) to provide the crude as a yellow solid which is carried onto the next step without determining a yield.

Step C: 3-Fluoro-2-methyl-4-phenoxyaniline

Iron powder (4.5 g, 80.6 mmol) and NH₄Cl (4.5 g, 84.1 mmol) were addedportion wise to a solution of 2-fluoro-3-methyl-4-nitro-1-phenoxybenzene(product from step B) in EtOH (60 mL) and H₂O (20 mL) at rt. Theresulting brown suspension was stirred at reflux during 2 hours. Thereaction mixture was quenched with water and extracted with ethylacetate. The organic phase was washed with water and brine, dried overNa₂SO₄ anhydrous, filtered and concentrated under reduced pressurefollowed by purification by flash chromatography (silica gel, PE/ethylacetate, 10/1) to obtain the title compound as a yellow solid (2.42 g,35%) MS (ESI): mass calcd. for C₁₃H₁₂FNO, 217.1; m/z found, 217.9[M+H]⁺.

Step D:2-Chloro-4-((3-fluoro-2-methyl-4-phenoxyphenyl)amino)nicotinonitrile

A mixture of 3-fluoro-2-methyl-4-phenoxyaniline (2.4 g, 11.0 mmol),2-chloro-4-iodonicotinonitrile (2.9 g, 11.0 mmol), DPEPhos (1.19 g, 2.2mmol), Pd(AcO)₂ (247.5 mg, 1.1 mmol), K₃PO₄ (4.68 g, 22.1 mmol) indioxane (50 mL) was heated at reflux under N₂ for 4 hr, thenconcentrated and purified by flash chromatography (silica gel, PE/ethylacetate, 10/1) to give the title compound as a yellow solid. (3.9 g,99.8%) MS (ESI): mass calcd. for C₁₉H₁₃ClFN₃O, 353.1; m/z found, 354.0[M+H]⁺.

Step E: Methyl3-amino-4-((3-fluoro-2-methyl-4-phenoxyphenyl)amino)thieno[2,3-b]pyridine-2-carboxylate

A mixture of2-chloro-4-((3-fluoro-2-methyl-4-phenoxyphenyl)amino)nicotinonitrile(3.9 g, 11.0 mmol), methyl 2-mercaptoacetate (2.3 g, 22.0 mmol) andNaOMe (1.17 g, 22.0 mmol) in MeOH (30 mL) was stirred at reflux for 16hours. The precipitate was collected by filtration, dried under vacuo togive the title compound without purification. (3.2 g, 69%). MS (ESI):mass calcd. for C₂₂H₁₈FN₃O₃S, 423.1; m/z found, 524.0 [M+H]⁺.

Step F: Methyl5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

CDI (4.9 g, 30.2 mmol) and Et₃N (0.5 mL) were added to a suspension ofMethyl3-amino-4-((3-fluoro-2-methyl-4-phenoxyphenyl)amino)thieno[2,3-b]pyridine-2-carboxylate(3.2 g, 7.56 mmol) in 1,4-dioxane (25 mL) at rt. The mixture was stirredat reflux for 3 hr, then concentrated and washed with MeOH to give thetitle compound as a yellow solid. (3.0 g, 99%) MS (ESI): mass calcd. forC₂₃H₁₆FN₃O₄S, 449.4; m/z found, 449.9 [M+H]⁺.

Step G:5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

A mixture of Methyl5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(3.0 g, 6.68 mmol) in MeOH/THF/H₂O (30/30/25 mL) was added LiOH.H₂O (1.4g, 33.4 mmol) and stirred at 60° C. overnight. The solvent was removedand acidified with 1N HCl. The title compound was collected byfiltration to give a tan solid. (2.6 g, 90%) MS (ESI): mass calcd. forC₂₂H₁₄FN₃O₄S, 435.4; m/z found, 435.9 [M+H]⁺.

Step H:(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A mixture of compound5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (650 mg, 1.49 mmol), tert-butyl (R)-3-aminopiperidine-1-carboxylate(598.03 mg, 2.99 mmol), Et₃N (301.6 mg, 2.99 mmol) and HATU (1.13 g,2.99 mmol) in DMF (5 mL) was stirred at rt for 3 hr. Water was added andthe precipitate isolated by filtration to give a pale yellow solid. Thesolid was dissolved in MeOH (8 mL) and acidified using HCl (8 mL). Theresulting mixture was heated to 50° C. and stirred for 30 min, and thenthe solvent was removed to give the title compound as a yellow solidwithout further purification (680 mg, 82%). MS (ESI): mass calcd. forC₂₇H₂₄FN₅O₃S, 517.2; m/z found, 518.0 [M+H]⁺.

Intermediate 19: (S)-2,3-Dimethoxypropanoic acid

Step A: Methyl (S)-2-hydroxy-3-methoxypropanoate

To a solution of methyl (S)-oxirane-2-carboxylate (1 g, 9.80 mmol) inmethanol (0.48 mL) was added was added Magnesiumtrifluoromethanesulfonate (790 mg, 2.45 mmol) at rt, and warmed to 40°C. for 16 hrs. Filtered and rinsed with DCM followed by concentration toobtain the title compound as a colorless oil (1.0 g, 76% yield).

Step B: Methyl (S)-2,3-diethoxypropanoate

A mixture of Methyl (S)-2-hydroxy-3-methoxypropanoate (900 mg, 6.7 mmol)in DCM (10 mL) was treated with methyl iodide (1.90 g, 13.4 mmol) andsilver oxide (2.32 g, 10 mmol) at rt. The mixture was warmed to 40° C.for 16 hours. Filtered and rinsed with DCM followed by concentration togive the title compound as a colorless oil (400 mg, 2.7 mmol, 40%yield).

Step C: (S)-2,3-Dimethoxypropanoic acid

A mixture of methyl (S)-2,3-diethoxypropanoate (400 mg, 2.7 mmol), andlithium hydroxide hydrate (454 mg, 11 mmol) in DME (4 mL) and water (1mL) stirred at rt for 16 hrs. Adjusted pH to <7, extracted with DCM, andconcentrated to give the title compound as a colorless oil withoutfurther purification or yield determination.

Intermediate 20: Benzyl 5-amino-2-methylpiperidine-1-carboxylate

Step A: Benzyl5-((tert-butoxycarbonyl)amino)-2-methylpiperidine-1-carboxylate

To a mixture of tert-butyl (6-methylpiperidin-3-yl)carbamate (900 mg,4.2 mmol) in DCM, was added triethylamine (848 mg, 8.4 mmol) and benzoylchloride (1.07 g, 6.3 mmol) which was allowed to stir at rt for 2 hrs.The crude reaction mixture was concentrated to a give the title compoundwithout further purification (900 mg, 61% yield). MS (ESI): mass calcd.for C₁₉H₂₈N₂O₄, 348.2; m/z found, 349.1 [M+H]⁺.

Step B: Benzyl 5-amino-2-methylpiperidine-1-carboxylate

A mixture of Benzyl5-((tert-butoxycarbonyl)amino)-2-methylpiperidine-1-carboxylate (900 mg,2.58 mmol), in methanol (5 mL), was added 1M HCl in methanol (5 mL). Themixture was allowed to stir at rt for 2 h. The crude reaction mixturewas concentrated to a give the title compound without furtherpurification (600 mg, 94% yield). MS (ESI): mass calcd. for C₁₄H₁₉NO₂,233.1; m/z found, 234.0 [M+H]⁺.

Intermediate 21: 2-[tert-Butoxycarbonyl(methyl)amino]acetic acid

Sodium hydride (6.85 g, 171 mmol) was added to a mixture of(tert-butoxycarbonyl)glycine (10 g, 57.1 mmol) and methyl iodide (75 g,528 mmol) in THF (600 mL) at 0° C. The mixture was slowly allowed towarm to rt overnight. Water (300 mL) was added and extracted into ethylacetate (2×500 mL). The aqueous layer was acidified to pH 3 with 1 M HClextracted with ethyl acetate (2×500 mL). The combined organic layer wasextracted with saturated aqueous sodium chloride (500 mL), dried(MgSO₄), filtration and concentrated to give the title compound as anoil (10 g, 91%).

Intermediate 22: tert-Butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate

A 20 mL microwave vial was charged with (R)-1-boc-3-aminopiperdine (5.0g, 25 mmol). The vial was sealed, evacuated, and back-filled with argonthree times. Methyl 2-mercaptoacetate (6.7 mL, 170 mmol) was added viasyringe in one portion and was heated to 150° C. in an oil bath. After 1h 35 minutes, the mixture was cooled to rt and purified by flash columnchromatography to yield a colorless oil (6.15 g. 90%).

Intermediate 23: (E)-2-Cyano-3-cyclopropylprop-2-enoyl chloride

Step A: (E)-2-Cyano-3-cyclopropylacrylic acid

Combined cyanoacetic acid (1.34 g, 15.7 mmol),cyclopropyanecarboxyaldehyde (1.0 mL, 13 mmol), ammonium acetate (101mg, 13.1 mmol) in acetic acid (10 ml) and warmed in a sand bath set at110° C. for 2 hrs. The reaction mixture was concentrate to a solid andsuspend in water (20 mL). The title compound was isolated by filtrationand dried under vacuum to give the title compound (1.3 g, 72%) as awhite solid.

Step B: (E)-2-Cyano-3-cyclopropylprop-2-enoyl chloride

To a suspension of (E)-2-cyano-3-cyclopropylacrylic acid (72.3 mg, 0.527mmol) in CDCl₃ (5.2 mL) was added 1-chloro-N,N,2-trimethylpropenylamine(0.084 mL, 1.01 g/mL, 0.635 mmol). The resulting clear colorlesssolution was mixed for 5 minutes before direct use in subsequentreactions.

Intermediate 24: tert-Butyl (3S,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate

Step A: (3S,4R)-tert-Butyl3-azido-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate

A solution of methanesulfonyl chloride (11.66 g, 101.8 mmol) in DCM wasadded to a mixture of tert-butyl(3R,4R)-3-[tert-butyl(dimethyl)silyl]oxy-4-hydroxy-pyrrolidine-1-carboxylate(26.9 g, 84.8 mmol) and triethylamine (16.6 mL, 119 mmol) in DCMdropwise at 0° C. The reaction mixture was stirred for 1.5 h at roomtemperature. The reaction mixture was taken up in water and extractedwith DCM. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated to dryness. The residue and sodium azide (11.2g, 170 mmol) in DMF was heated at 120° C. for 13 h. The reaction mixturewas poured into water and the mixture extracted with toluene. Theorganic layer was washed with brine, dried over anhydrous MgSO₄, andconcentrated to dryness. The residue was purified by flash columnchromatography to yield the title compound (13.5 g, 47%).

Step B: tert-Butyl(3S,4R)-3-amino-4-[tert-butyl(dimethyl)silyl]oxy-pyrrolidine-1-carboxylate

A solution of (3S,4R)-tert-butyl3-azido-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate (13.5g, 39.4 mmol) and Pd/C (10% on carbon, 400 mg, 0.376 mmol) in ethanol(150 mL) was hydrogenated under H₂-gas for 2 hours. The reaction mixturewas filtered over Celite and concentrated to dryness to yield the titlecompound (12.36 g, 99.08% yield).

Step C: tert-Butyl (3S,4R)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate

To a solution of tert-butyl(3S,4R)-3-amino-4-[tert-butyl(dimethyl)silyl]oxy-pyrrolidine-1-carboxylate(12.15 g, 38.39 mmol) in THF was added TBAF (52.2 mL, 52.2 mmol). Thereaction mixture was stirred at room temperature for 4 h. The reactionmixture was concentrated to dryness and water was added. The mixture wasextracted with ethyl acetate and the organic layer was washed with waterand brine several times. The water layer was extracted several timeswith chloroform. NaCl was added to the water layer and it was againextracted with chloroform. The combined organic layers were dried overanhydrous MgSO₄, filtered, and concentrated to dryness. The residue waspurified by flash column chromatography to yield the title compound (7.8g, 100% yield).

Intermediate 25:4-((4-(2-((tert-Butyldimethylsilyl)oxy)phenoxy)-2-methylphenyl)amino)-2-chloronicotinonitrile

Step A: 2-(3-Methyl-4-nitrophenoxy)phenol

The title compound was prepared in a manner analogous to Intermediate27, Step A, using pyrocatechol.

Step B: tert-Butyldimethyl(2-(3-methyl-4-nitrophenoxy)phenoxy)silane

To a solution of 2-(3-methyl-4-nitrophenoxy)phenol (4.90 g, 20 mmol) inDCM (40 mL) were added Et₃N (3.03 g, 30 mmol) and TBSCl (3.31 g, 22mmol) and stirred at room temperature for 3 hours. The reaction mixturewas dispersed between DCM and saturated NH₄Cl aqueous solution. Theorganic layer was collected, condensed and purified by flashchromatography eluting with PE/EA to yield the title compound (4.10 g,57% yield)

Step C:4-((4-(2-((tert-Butyldimethylsilyl)oxy)phenoxy)-2-methylphenyl)amino)-2-chloronicotinonitrile

The title compound was prepared in a manner analogous to Intermediate27, Steps B-C, usingtert-butyldimethyl(2-(3-methyl-4-nitrophenoxy)phenoxy)silane in step B.MS (ESI): mass calcd. for C₂₅H₂₈ClN₃O₂Si, 465.2; m/z found, 466.0[M+H]+.

Intermediate 26: 3,5-Difluoro-4-nitrophenol

To a solution of 3,5-difluorophenol (20.45 g, 157.2 mmol) in DCM (225mL) was added fuming nitric acid (>90%, 7.86 mL, 157 mmol) dropwise over10 minutes. The resulting orange solution was stirred in an ice bath for50 min. The mixture was poured into water (200 mL) and the phasesseparated. The aqueous phase was extracted with DCM (50 mL) and EtOAc(2×50 mL). The combined organic extracts were dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby flash column chromatography to yield the title compound (11.24 g,40.8% yield) as a yellow solid. MS (ESI): mass calcd. for C₆H₃F₂NO₃,175.0; m/z found, 174 [M−H]⁻.

Intermediate 27:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

Step A: 2-Methyl-1-nitro-4-phenoxybenzene

To a round bottom flask were added phenol (42.5 g, 452 mmol), K₂CO₃ (125g, 905 mmol), and DMF (500 mL). To the reaction mixture was added5-fluoro-2-nitrotoluene (70.2 g, 452 mmol) and the reaction was stirredat 80° C. for 16 h under N₂. The reaction was diluted with saturatedNH₄Cl and extracted with MTBE (3×400 mL). The organic layers werecombined, dried over anhydrous Na₂SO₄, filtered, and concentrated todryness to yield the title compound (100 g, 92% yield) as a brown oil.

Step B: 2-Methyl-4-phenoxyaniline

To a solution of 2-methyl-1-nitro-4-phenoxybenzene (100 g, 436 mmol) inEtOH/H₂O (3:1 ratio, 2000 mL) were sequentially added NH₄Cl (117 g, 2180mmol) and Fe (97 g, 1700 mmol). The reaction mixture was heated toreflux for 2 h, then the reaction was cooled to 25° C. and concentratedto dryness. To the residue was added water and EtOAc and the organiclayer was separated, washed with saturated NaHCO₃ and saturated brine,dried over anhydrous MgSO₄, filtered, and concentrated to dryness toyield the title compound (82 g, 90% yield).

Step C: 2-Chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrile

To a round bottom flask under a N₂ atmosphere were added2-methyl-4-phenoxyaniline (30 g, 150 mmol),2-chloro-4-iodopyridine-3-carbonitrile (51.6 g, 195 mmol), and dioxane(200 mL), followed by bis(2-diphenylphosphinophenyl)ether (DPEphos) (16g, 30 mmol), Pd(OAc)₂ (3.36 g, 15 mmol), and K₃PO₄ (89 g, 420 mmol). Thereaction mixture was stirred at 100° C. overnight. The reaction mixturewas filtered and purified flash column chromatography to yield the titlecompound (32 g, 63% yield) as a yellow solid.

Step D: Methyl3-amino-4-(2-methyl-4-phenoxyanilino)thieno[2,3-b]pyridine-2-carboxylate

To a round bottom flask were added2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrile (36 g, 107mmol) in MeOH (150 mL). To this solution was added NaOMe (14.5 g, 268mmol) in MeOH (30 mL), followed by methyl 2-sulfanylacetate (23 g, 217mmol). The reaction mixture was refluxed overnight. The reaction mixturewas cooled and the yellow precipitate was filtered off, washed withMeOH, and dried to yield the title compound (30 g, 75% yield) as ayellow solid.

Step E: Methyl5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

To a round bottom flask were added methyl3-amino-4-(2-methyl-4-phenoxyanilino)thieno[2,3-b]pyridine-2-carboxylate(30.6 g, 75.5 mmol), carbonyldiimidazole (49 g, 300 mmol), and1,4-dioxane (500 ml). The reaction was stirred at reflux overnight. Thenthe reaction mixture was concentrated to dryness and to the residue wasadded to MeOH (200 mL) and the precipitate that formed was filtered offand dried to yield the title compound (28.1 g, 86%) as a yellow solid.

Step F:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

To a round bottom flask were added methyl5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(9.2 g, 21 mmol), lithium hydroxide (4.47 g, 106 mmol), THF (200 mL),MeOH (200 mL), and water (50 mL). The reaction mixture was stirred at50° C. for 15 h. The mixture was concentrated to dryness and dilutedwith H₂O. The pH was adjusted to 2 with 1 M HCl and the precipitate wasfiltered and dried to yield the title compound (8.1 g, 91% yield) asyellow solid. MS (ESI): mass calcd. for C₂₂H₁₅N₃O₄S, 417.1; m/z found,418.1 [M+H]⁺.

Intermediate 28: 2-((3-(3-Methyl-4-nitrophenoxy)benzyl)oxy)benzonitrile

Step A: 3-(3-Methyl-4-nitrophenoxy)benzaldehyde

4-fluoro-2-methyl-1-nitrobenzene (13 mL, 106.6 mmol),3-hydroxybenzaldehyde (19.8 mL, 162 mmol) and K₂CO₃ (30.1 g, 217.9 mmol)were dissolved in DMF (123 mL) at rt under an atmosphere of argon. Themixture was warmed in a sand bath at 110° C. under N₂ for 5 hours.Cooled, filtered and extracted into ether partitioning away from a brinesolution. The title compound was purified by silica chromatography(ethyl acetate/hexanes followed by DCM/methanol) (9.83 g, 36%) MS (ESI):mass calcd. for C₁₄H₁₁NO₄, 257.1; m/z found, 258.0 [M+H]⁺.

Step B: (3-(3-Methyl-4-nitrophenoxy)phenyl)methanol

To a scintillation vial containing3-(3-methyl-4-nitrophenoxy)benzaldehyde (13 g, 50.5 mmol) was added astir bar and the vessel was purged with N2. Dry MeOH (125 mL, dried overhot 3A sieves) was added via a syringe filter and the suspension wascooled to −10° C. Sodium borohydride (1.1 g, 29 mmol) was added in oneportion with mixing and the reaction was allowed to warm to rt over 30min. The title compound was isolated by extracting into ethyl acetatefrom a solution of saturated aqueous NH₄Cl followed by drying overNa₂SO₄, filtration and concentration. (8.66 g, 66%) C₁₄H₁₃NO₄. ¹H NMR(500 MHz, Methanol-d4): δ 8.08-8.01 (m, 1H), 7.46-7.37 (m, 1H),7.26-7.20 (m, 1H), 7.14-7.08 (m, 1H), 7.04-6.97 (m, 1H), 6.97-6.92 (m,1H), 6.92-6.87 (m, 1H), 4.62 (s, 2H), 2.55 (s, 3H).

Step C: 2-((3-(3-Methyl-4-nitrophenoxy)benzyl)oxy)benzonitrile

(3-(3-methyl-4-nitrophenoxy)phenyl)methanol (8.13 g, 31.4 mmol),triphenylphosphine (9.97 g, 37.6 mmol) and DIAD (6.5 mL, 31.4 mmol) weredissolved in dry THF (118 mL) under an atmosphere of N2. The suspensionwas cooled to −10° C. and 2-hydroxybenzonitrile (4.5 g, 37.6 mmol) wasadded in one portion with mixing. The reaction was allowed to warm tort, followed by heating to 80° C. for 3 hours, 40° C. for 33 hours and80° C. for 1.5 hours. Concentrated crude reaction mixture onto silicaand eluted through a plug of silica in a fritted funnel with ethylacetate/hexanes, 4/1 to give the title compound. (8.65 g, 77%) MS (ESI):mass calcd. for C₂₁H₁₆N₂O₄, 360.1; m/z found, 361.0 [M+H]⁺. ¹H NMR (500MHz, Methanol-d4): δ 8.02 (d, J=9.0 Hz, 1H), 7.68-7.55 (m, 2H),7.53-7.41 (m, 1H), 7.41-7.29 (m, 1H), 7.29-7.14 (m, 2H), 7.14-7.01 (m,2H), 6.99-6.85 (m, 2H), 5.27 (s, 2H), 2.53 (s, 3H).

Intermediate 29: tert-Butyl(3R,5S)-3-amino-5-methoxypiperidine-1-carboxylate

Step A: (3R,5S)-tert-Butyl 3-azido-5-hydroxypiperidine-1-carboxylate

The title compound was prepared using the method for Intermediate 2,steps A-J. Mass calcd. for C₁₀H₁₈N₄O₃, 242.1.1; ¹H NMR (400 MHz, CDCl₃):δ 3.85-3.68 (m, 3H), 3.60-3.49 (m, 1H), 3.16-3.00 (m, 2H), 2.38-2.07 (m,3H), 1.65-1.59 (m, 1H), 1.44 (s, 9H).

Step B: tert-Butyl (3R,5S)-3-azido-5-methoxypiperidine-1-carboxylate

A solution of (3R,5S)-tert-butyl3-azido-5-hydroxypiperidine-1-carboxylate (200 mg, 0.83 mmol) and Ag₂O(152 mg, 1.24 mmol) in CH₃I (4 mL) was reacted at 60° C. for 16 h,filtered, and concentrated to dryness to give the title compound as acolorless oil (200 mg, 95%). Mass calcd. for C₁₁H₂₀N₄O₃, 256.2; ¹H NMR(400 MHz, CDCl₃): δ 4.39-4.00 (m, 3H), 3.37 (s, 3H), 3.36-3.29 (m, 1H),3.24-3.15 (m, 1H), 2.68-2.31 (m, 3H), 1.44 (s, 9H), 1.37-1.29 (m, 1H).

Step C: tert-Butyl (3R,5S)-3-amino-5-methoxypiperidine-1-carboxylate

A solution of tert-butyl(3R,5S)-3-azido-5-methoxypiperidine-1-carboxylate (200 mg, 0.78 mmol)and Pd/C (10% on carbon, 20 mg) in MeOH (10 mL) was reacted at rt underH₂ for 16 h. The reaction mixture was filtered and concentrated todryness to give the title compound (170 mg, 95%), which was used in thenext step without purification. MS (ESI): mass calcd. for C₁₁H₂₂N₂O₃,230.30; m/z found, 231.1 [M+H]⁺.

Intermediate 30: 2-Fluoro-3-methylbut-2-enoic acid

Step A: Ethyl 2-diethoxyphosphoryl-2-fluoroacetate

Ethyl 2-bromo 2-fluoroacetate (5.0 g, 27 mmol) was added totriethylphosphite (13 mL) and heated at 130° C. for 23 h. The resultingmixture was distilled under low pressure (1.4 mbar, 75-110° C.) to givethe title compound as a yellowish oil (6.0 g, 92%).

Step B: Ethyl 2-fluoro-3-methylbut-2-enoate

To a dry 250 mL 2-neck round bottom flask that was purged with N₂ wasadded ethyl 2-diethoxyphosphoryl-2-fluoroacetate (500 mg, 2.07 mmol).Anhydrous THF (20 mL) was added and the reaction mixture was cooled to−70° C., then BuLi (2.5 M in Hexane, 1 mL) was added dropwise. Thereaction mixture was stirred for 2 h at −70° C., then acetone (1 mL) wasadded and the reaction was warmed to rt and stirred overnight. Thereaction was quenched by addition of an NH₄Cl solution and extractedwith EtOAc. The organic layers was washed with brine, dried overanhydrous Na₂SO₄, and concentrated to dryness to give the title compoundas a yellow oil (266 mg, 88.1% yield).

Step C: 2-Fluoro-3-methylbut-2-enoic acid

To a solution of ethyl 2-fluoro-3-methylbut-2-enoate (266 mg, 1.82 mmol)in dioxane (5 mL) and water (5 mL) was added NaOH (291.3 mg, 7.281 mmol)and was stirred for 10 min at 60° C. The mixture was acidified with 2 MHCl to pH 2 and extracted with DCM. The organic phase was washed withbrine, dried over anhydrous MgSO₄, and concentrated to dryness to givethe title compound as a yellow oil (181 mg, 84%).

Intermediate 31:2-Chloro-4-(2-methyl-4-tetrahydropyran-4-yloxyanilino)pyridine-3-carbonitrile

Step A: Tetrahydro-2H-pyran-4-yl methanesulfonate

To a solution of tetrahydro-2H-pyran-4-ol (2 g, 20 mmol) in DCM (20 mL)at 0° C. was added DIEA (3 g, 23.5 mmol), and methanesulfonyl chloride(2.46 g, 21.5 mmol). The reaction mixture was stirred at 0° C. for 1 hr,then at room temperature for 1.5 hrs. The mixture was poured into water,extracted into DCM. The organic layer was separated, washed with water,brine, dried over Na₂SO₄, and concentrated to give the title compound.(3.72 mg, quantitative).

Step B: 4-(3-Methyl-4-nitrophenoxy)tetrahydro-2H-pyran

Tetrahydro-2H-pyran-4-yl methanesulfonate (3.53 g, 19.6 mmol) wasdissolved in DMF (40 mL), followed by the addition of Cs₂CO₃ (9.57 g,29.4 mmol) and 3-methyl-4-nitrophenol (3 g, 19.6 mmol). The mixture washeated at 120° C. for 3 h, then cooled to rt, and diluted with water andextracted into EA. The combined organic layers were washed with brineand concentrated, then purified by chromatography with DCM/MeOH to getthe target compound as a white solid. (2.87 g, 62%) MS (ESI): masscalcd. for C₁₂H₁₅NO₄, 237.1; m/z found, 238.3 [M+H]⁺.

Step C: 2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)aniline

4-(3-methyl-4-nitrophenoxy)tetrahydro-2H-pyran (1.1 g, 4.6 mmol) wastreated with Palladium on carbon (25 mg, 0.2 mmol) in methanol (20 mL)with a positive pressure of hydrogen gas at rt for 18 hours. The titlecompound was isolated after filtering through a pad of Celite andconcentrating to give a brown solid. (0.81 g, 84%) MS (ESI): mass calcd.for C₁₂H₁₇NO₂, 207.1; m/z found, 208.1 [M+H]⁺.

Step D:2-Chloro-4-(2-methyl-4-tetrahydropyran-4-yloxyanilino)pyridine-3-carbonitrile

2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)aniline (0.81 g, 3.9 mmol),2-chloro-4-iodonicotinonitrile (1.3 g, 5.1 mmol), Cs₂CO₃ (2.54 g, 7.8mmol), DPEPhos (0.42 g, 0.8 mmol), Pd(OAc)₂ (87.5 mg, 0.4 mmol) weredissolved in 1,4-dioxane (30 mL). The mixture was stirred at 80° C.overnight. The title compound was purified by flash chromatography(PE/EA) to give a yellow solid. (1.03 g, 80%) MS (ESI): mass calcd. forC₁₈H₁₈ClN₃O₂, 343.1; m/z found, 344.1 [M+H]⁺.

Intermediate 32:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride

To a solution of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) (500 mg, 1.2 mmol) in anhydrous DCM (20 mL) wasadded 2-drops of DMF and it was cooled to 0° C. Next, oxalyl dichloride(762 mg, 6 mmol) was added slowly and it was stirred at 40° C.overnight, concentrated to dryness, and the residue was used in the nextstep without further purification or determined yield.

Intermediate 33: (Z)-3-Acetamidoprop-2-enoic acid

Step A: Ethyl (Z)-3-acetamidoprop-2-enoate

To a solution of ethyl prop-2-ynoate (1.246 g, 12.70 mmol), acetamide(500 mg, 8.5 mmol), TFA (4.8 g, 42 mmol), and NaOAc (1.46 g, 16.9 mmol)in toluene (15 mL) was added Pd(OAc)₂ (95 mg, 0.42 mmol) at rt under N₂and stirred at 70° C. overnight, concentrated to dryness, and purifiedby flash column chromatography to give the title compound as an oil (470mg, 35% yield).

Step B: (Z)-3-Acetamidoprop-2-enoic acid

A solution of ethyl (Z)-3-acetamidoprop-2-enoate and LiOH.H₂O in THF/H₂O(1/1) was stirred at 50° C. for 1 h, then the solution was acidifiedwith 1 M HCl and extracted with EtOAc, combining the organic layers, andconcentrated to dryness to give the title compound, which was usedwithout further purification in the next step.

Intermediate 34:2-Chloro-4-((4-cyclobutoxy-2-methylphenyl)amino)nicotinonitrile

The title compound was prepared using Method 1, steps A-C in Example 1,and using 3-methyl-4-nitro-phenol and bromocyclobutane in place ofphenol and 5-fluoro-2-nitrotoluene in step A, to yield the titlecompound. MS (ESI): mass calcd. for C₁₇H₁₆ClN₃O, 313.1; m/z found, 314.0[M+H]⁺.

Intermediate 35: (4-Phenoxyphenyl)methanamine

A solution of 4-phenoxybenzaldehyde (2.0 g, 10 mmol), hydroxylaminehydrochloride (700 mg, 10 mmol), EtOH (20 ml), and water (1 ml) wasstirred at room temperature overnight. To the reaction mixture wereadded 10 N HCl (1 ml) and of Pd/C (10% on carbon, 320 mg) and wasstirred under hydrogen for 30 min. The reaction mixture was filtratedthrough Celite and concentrated to dryness. The residue was purified byflash column chromatography to give the title compound as a white solid(1.5 g, 75% yield).

Intermediate 36:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using Method 1, steps A-H (includingChiral Resolution Method A after step F to obtain the *S atropisomer) inExample 1, and using tert-butyl (3R)-3-aminocyclopentanecarboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate instep G, to yield the title compound. MS (ESI): mass calcd. forC₂₆H₂₃N₅O₃S, 485.2; m/z found, 486.1 [M+H]⁺.

Intermediate 37: (E)-4-Methylsulfanylbut-2-enoic acid

Step A: Methyl (E)-4-methylsulfanvlbut-2-enoate

To a solution of methyl (E)-4-bromobut-2-enoate (1.507 g, 8.418 mmol) inMeCN (50 mL) was added 15% aqueous solution of NaSMe (0.59 g, 8.4 mmol)in water (4 mL) at −40° C. The resulting mixture was warmed at 0° C.over a period of 1 h. The reaction was dispersed between EtOAc andwater, the organic layer was collected, and concentrated to dryness togive the title compound (1.231 g, 100.0% yield) and was used in the nextstep without further purification.

Step B: (E)-4-Methylsulfanvlbut-2-enoic acid

A solution of methyl (E)-4-methylsulfanylbut-2-enoate (1.231 g 8.418mmol) and LiOH.H₂O (1.413 g, 33.67 mmol) in THF (15 mL) and water (15mL) was stirred at room temperature for 6 hours. The reaction wasadjusted to pH=3 using a 1 M aqueous solution of HCl and was dispersedbetween EtOAc and water. The organic layer was collected andconcentrated to dryness to give the title compound (0.556 g, 50.0%yield), which was used in the next step without further purification.

Intermediate 38:(Z)-4-[tert-Butoxycarbonyl(methyl)amino]-2-fluoro-but-2-enoic acid

Step A: Ethyl 2-diethoxyphosphoryl-2-fluoro-acetate

A solution of ethyl 2-bromo 2-fluoroacetate (5.0 g, 27 mmol) intriethylphosphite (13 mL) was heated at 130° C. for 23 h. The resultingmixture was distilled under low pressure (1.4 mbar, 75-110° C.) to givethe title compound as a yellowish oil (6.0 g, 92%).

Step B: (Z)-4-[tert-Butoxycarbonyl(methyl)amino]-2-fluoro-but-2-enoicacid

Ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (2.0 g, 8.3 mmol) wasplaced in THF (5 mL) and cooled to 0° C. in ice-bath. Next, NaH (198 mg,8.26 mmol) was added and stirred for 30 min at 0° C. tert-ButylN-methyl-N-(2-oxoethyl)carbamate (0.579 g, 3.34 mmol) was added to thereaction mixture slowly and the reaction mixture was allowed to warm toroom temperature over 2 h. The reaction was quenched by the addition ofDCM and water. The organic layer was collected and washed with brine,dried over anhydrous MgSO₄, and concentrated to dryness. The residue wasdissolved in dioxane (5 mL) and water (5 mL), and NaOH (1.321 g, 33.03mmol) was added and was reacted for 10 min at rt. The mixture wasacidified with 2 M HCl to pH-2 and extracted with DCM. The organiclayers were washed with brine, dried over anhydrous MgSO₄, andconcentrated to dryness to give the title compound (500 mg, 26%).

Intermediate 39: (E/Z)-2-Chloro-3-cyclopropyl-prop-2-enoic acid

Step A: Ethyl 2,2-dichloro-2-diethoxyphosphoryl-acetate

A solution of 5% sodium hypochlorite (185 mL) was adjusted to pH 7.1with 3 N HCl (10 mL) and ethyl 2-diethoxyphosphorylacetate (5.60 g, 25.0mmol) was added drop wise at 0° C. with vigorous stirring over 30 min.After complete addition, the mixture was stirred for 5 min at rt andextracted with hexanes. The reaction mixture was concentrated to drynessgave the title compound as a colorless oil (0.86 g, 12% yield).

Step B: Ethyl 2-chloro-2-diethoxyphosphoryl-acetate

A solution of ethyl 2,2-dichloro-2-diethoxyphosphoryl-acetate (0.86 g,2.9 mmol) in EtOH (6 mL) was cooled to 0° C. A solution of sodiumsulfite (0.74 g, 5.9 mmol) in water (20 mL) was added at a rate that thetemperature could be kept around 15° C. After the end of the additionthe turbid solution was stirred at room temperature for 20 minutesbefore being extracted with chloroform (4×15 mL). The combined extractswere dried over anhydrous MgSO₄ and concentrated to dryness to give thetitle compound as a yellow oil (0.47 g, 62% yield).

Step C: Ethyl (E/Z)-2-chloro-3-cyclopropyl-prop-2-enoate

To a solution of NaH (60% in oil, 87 mg, 3.6 mmol) in THF (10 mL) at 0°C. was added ethyl 2-chloro-2-diethoxyphosphoryl-acetate (0.47 g, 1.8mmol) dropwise and stirred at 0° C. for 1 h. Thencyclopropanecarbaldehyde (127 mg, 1.82 mmol) was added dropwise andstirred at 0° C. for 1 h. The mixture was quenched with saturated NH₄Cl,extracted with EtOAc, washed with brine, dried over anhydrous MgSO₄, andconcentrated to dryness to give the title compound as a yellow liquid(0.24 g, 76% yield).

Step D: (E/Z)-2-Chloro-3-cyclopropyl-prop-2-enoic acid

To a solution of ethyl (EZ)-2-chloro-3-cyclopropyl-prop-2-enoate (0.24g, 1.4 mmol) in dioxane (5 mL) and water (5 mL) was added KOH (0.385 g,6.87 mmol) and the mixture was stirred at 60° C. for 2 h. The pH of themixture was adjusted to about 2, extracted with EtOAc, dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness to give thetitle compound as a light yellow solid (0.13 g, 65% yield), which wasused in the next step directly.

Intermediate 40:4-Oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride

To a 50 mL flask with a stir bar were added4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 58) (1.0 g, 2.5 mmol) and thionyl chloride (10.0 mL,137 mmol) and was warmed in a sand bath to reflux for 1 hour. Thereaction mixture was concentrated to dryness and added DCM was added andthe reaction was concentrated to dryness to give the title compound(1.046 g, 100.0% yield), which was used without further purification.

Intermediate 41:(R)-5-(2-Methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using2,3,4,5,6-pentadeuteriophenol in place of phenol in step A and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G.

Intermediate 42: (E)-3-Cyclopropyl-2-methyl-prop-2-enoic acid

Step A: Ethyl (E)-3-cyclopropyl-2-methyl-prop-2-enoate

A solution of ethyl 2-diethoxyphosphorylpropanoate (2.38 g, 10.0 mmol)in THF (30 mL) was cooled to −78° C. and n-BuLi (2.4 N, 4.58 mL) wasadded dropwise and stirred at −78° C. for 1 h. Thencyclopropanecarbaldehyde (0.70 g, 10 mmol) was added dropwise andstirred at −78° C. for 1 h. The mixture was quenched with saturatedaqueous NH₄Cl and extracted with EtOAc, washed with brine, dried overanhydrous Na₂SO₄, and concentrated to dryness to give the title compoundas a yellow liquid (1.13 g, 73.3% yield). MS (ESI): mass calcd. forC₉H₁₄O₂, 154.1; m/z found, 155.1 [M+H]⁺.

Step B: (E)-3-Cyclopropyl-2-methyl-prop-2-enoic acid

To a solution of ethyl (E)-3-cyclopropyl-2-methyl-prop-2-enoate (1.13 g,7.33 mmol) in dioxane (15 mL) and water (15 mL) was added KOH (2.056 g,36.64 mmol) and the mixture was stirred at 60° C. for 2 h. The pH of themixture was adjusted to about 2, then extracted with EtOAc, dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness to give thetitle compound as light yellow solid (0.77 g, 83% yield), which was usedin the next step directly. MS (ESI): mass calcd. for C₇H₁₀O₂, 126.1; m/zfound, 127.1 [M+H]+.

Intermediate 43: 1-[(3R)-3-Amino-1-piperidyl]-2-(dimethylamino)ethanone

Step A: tert-ButylN-[(3R)-1-[2-(dimethylamino)acetyl]-3-piperidyl]carbamate

A solution of tert-butyl (3R)-3-aminopiperidine-1-carboxylate (400 mg,2.0 mmol), 2-(dimethylamino)acetic acid (226 mg, 2.19 mmol), HATU (911mg, 2.40 mmol), and triethylamine (0.557 mL, 4.00 mmol) in DMF (5 mL)was stirred at rt overnight, then poured into water. The mixture wasextracted with EtOAc, the combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated todryness to give the title compound as a yellow oil (399 mg, 70%).

Step B: 1-[(3R)-3-Amino-1-piperidyl]-2-(dimethylamino)ethanone

A solution of tert-butylN-[(3R)-1-[2-(dimethylamino)acetyl]-3-piperidyl]carbamate (200 mg, 0.70mmol) in 2 M HCl in MeOH (2 mL) was stirred at rt overnight. Thereaction was concentrated to dryness and the residue was used in nextstep without further purification (150 mg, quantitative). MS (ESI): masscalcd. for C₉H₁₉N₃O, 185.2; m/z found, 186.1 [M+H]⁺.

Intermediate 44: (E)-2-Cyano-4,4-dimethyl-pent-2-enoic acid or(E)-2-cyano-4,4-dimethylpent-2-enoic acid

A stirred solution of 2-cyanoacetic acid (1.70 g, 20 mmol),pivalaldehyde (1.72 g, 20 mmol) and NH₄OAc (60 mg, 0.8 mmol) in toluenewas heated to reflux with Dean-Stark removal of water. When generationof water ceased, the mixture was cooled to room temperature andconcentrated under reduced pressure to yield the title product as ayellow solid (2.13 g, 69% yield).

Intermediate 45: 1-Bromo-2-fluoro-5-methyl-4-nitrobenzene

A solution of 4-bromo-5-fluoro-2-methylaniline (10.2 g, 50 mmol) and3-chlorobenzenecarboperoxoic acid (34.5 g, 200 mmol) in DCE (10 mL) wasstirred under nitrogen at reflux for 2 hours. After cooling to rt, themixture was dispersed between DCM and saturated aqueous Na₂SO₃ solution.The organic layer was collected, concentrated to dryness and purified byflash column chromatography to give the title compound as a brown oil(7.02 g, 60.0% yield).

Intermediate 46: [1,1′-Biphenyl]-3-amine

To a solution of phenylboronic acid (12.193 g, 100.00 mmol) in MeOH (150mL) were added sequentially Na₂CO₃ (21.198 g, 200.00 mmol) and3-bromoaniline (17.202 g, 100.00 mmol), and then Pd(OAc)₂ (562 mg, 2.50mmol) was added and the reaction was heated to reflux until a blacksuspension appeared. The reaction was cooled to room temperature,diluted with MeOH, and the black precipitate was removed by filtration.The filtrate was concentrated to dryness and the residue was added towater and DCM. The organic phase was collected, dried over anhydrousNa₂SO₄, and concentrated to dryness to give the title compound (18.373g, 100.00% yield) as a brown oil. MS (ESI): mass calcd. for C₁₂H₁₁N,169.22; m/z found, 170.0 [M+H]⁺.

Intermediate 47: 3-(Tetrahydro-2H-pyran-4-yl)aniline

Step A: 3-(3,6-Dihydro-2H-pyran-4-yl)aniline

A solution of 3-bromoaniline (0.9 mL, 8.10 mmol),3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester (5.11 g, 24.3 mmol)and X-phos-palladium precatalyst generation 1 (163 mg, 0.203 mmol) indioxane (6.1 mL) and 0.5 M K₃PO₄H₂O (12.2 mL) was stirred at 90° C. for16 h. The reaction mixture was concentrated to dryness and the residuewas purified by FCC (SiO₂, 0-10% MeOH (2 N NH3)/DMC) to give the titlecompound (320 mg, 17%).

Step B: 3-(Tetrahydro-2H-pyran-4-yl)aniline

A solution of 3-(3,6-dihydro-2H-pyran-4-yl)aniline (2.0 g, 4.87 mmol) in1:1 MeOH:DCM (97 mL) was passed through an H-cube® hydrogenation flowreactor (recycling @ 80° C., 1 atm, 1.5 mL/min, 10% Pd/C) for 16 h. Thesolution as concentrated then purified (FCC, EtOAc-hexanes) to give thetitle compound (548 mg, 63%) as a white solid. MS (ESI): mass calcd. forC₂₁H₂₁N₅O₂S, 407.1; m/z found, 408 [M+H]⁺.

Intermediate 48: 3-Methyl-2-phenylpyridin-4-amine

Step A: 3-Methyl-2-phenylpyridin-4-amine

To a solution of 4-bromo-2-chloro-3-methylpyridine (2.20 g, 10.7 mmol),tert-butyl carbamate (1.248 g, 10.66 mmol), Pd(dppf)Cl₂ (435 mg, 0.533mmol), Xantphos (616 mg, 1.07 mmol), and Cs₂CO₃ (6.926 g, 21.31 mmol) indioxane (60 mL) was heated at reflux under N₂ overnight. The reactionwas concentrated to dryness and the residue was purified by flash columnchromatography to give white solid that was used directly in the nextstep.

Step B: 3-Methyl-2-phenylpyridin-4-amine

3-Methyl-2-phenylpyridin-4-amine was dissolved in dioxane and H₂O,Pd(dppf)Cl₂ (435 mg, 0.533 mmol), and Na₂CO₃ (2.259 g, 21.31 mmol) wereadded and stirred at reflux overnight. The reaction was concentrated todryness and the residue was purified by flash column chromatography togive yellow solid. The yellow solid was dissolved in HCl and MeOH andstirred at 60° C. for 30 min. Then 1 M NaOH was added and was extractedwith EtOAc (30 mL×3) and concentrated to dryness to give the titlecompound (700 mg, 36% yield) as a pale yellow solid. MS (ESI): masscalcd. for C₁₂H₁₂N₂, 184.24; m/z found, 185.1 [M+H]⁺.

Intermediate 49: 2-Methyl-6-phenoxypyridin-3-amine

Step A: 2-methyl-3-nitro-6-phenoxypyridine

A round bottom flask containing 6-chloro-2-methyl-3-nitropyridine (50.1g, 290 mmol) and CH₃CN (230 mL) was cooled at 0° C. Phenol (41.0 g, 436mmol) was added followed by Cs₂CO₃ (148 g, 454 mmol). The reactionmixture was allowed to warm to room temperature and stirred for 15 h.The mixture was transferred to a 2 L Erlenmeyer flask, then diluted withwater to a total volume of 1.8 L. The resulting suspension was stirredat room temperature for 10 min, then the solid was isolated byfiltration, rinsed with water and dried to yield the title compound(64.7 g, 97% yield) as a brown solid. MS (ESI): mass calcd. forC₁₂H₁₀N₂O₃, 230.07; m/z found, 231.0 [M+H]⁺.

Step B: 2-methyl-6-phenoxypyridin-3-amine

A round bottom flask containing 2-methyl-3-nitro-6-phenoxypyridine (64.7g, 281 mmol) was treated with EtOH (500 mL) and a suspension of 10% Pd/C(4.17 g) in EtOH (300 mL). The mixture was degassed under vacuum andvented to an atmosphere of H₂. The reaction was stirred vigorously atroom temperature for 7 h. The reaction mixture was filtered throughcelite, the filtrate was concentrated to about 400 mL, then water wasadded slowly until the total volume was 1.5 L. The resulting precipitatewas filtered, and the filter cake was rinsed with water then dried undervacuum to provide the title compound (50.5 g, 90%) as an off-whitesolid. MS (ESI): mass calcd. for C₁₂H₁₂N₂O, 200.09; m/z found, 201.0[M+H]⁺.

Intermediate 50:(2R)-1-[(3R)-3-Amino-1-piperidyl]-3-methoxy-2-methyl-propan-1-one

Step A: tert-ButylN-[(3R)-1-[(2S)-2-hydroxypropanoyl]-3-piperidyl]carbamate

To a solution of (2R)-3-hydroxy-2-methyl-propanoic acid (78 mg, 0.75mmol), HATU (342 mg, 0.90 mmol), and triethylamine (0.157 mL, 1.12 mmol)in DMF (3 mL) was added tert-butyl N-[(3R)-3-piperidyl]carbamate and thereaction was stirred at rt overnight. The reaction mixture was purifiedusing flash column chromatography to give the title compound as acolorless liquid (138 mg, 68%).

Step B: tert-ButylN-[(3R)-1-[(2R)-3-methoxy-2-methyl-propanoyl]-3-piperidyl]carbamate

A solution of tert-butylN-[(3R)-1-[(2S)-2-hydroxypropanoyl]-3-piperidyl]carbamate (128 mg, 0.447mmol), Ag₂O (311 mg, 1.34 mmol), MeI (1 mL), and DCM (2 mL) was spargedwith N2 and stirred at 40° C. for 3 days. The mixture was filteredthrough a pad of Celite and the filtrated was concentrated to dryness togive the title compound (121 mg, 91%), was used in next step withoutfurther purification.

Step C:(2R)-1-[(3R)-3-Amino-1-piperidyl]-3-methoxy-2-methyl-propan-1-one

To a solution of 2 M HCl in MeOH (2 mL) was added tert-butylN-[(3R)-1-[(2R)-3-methoxy-2-methyl-propanoyl]-3-piperidyl]carbamate (121mg, 0.403 mmol). The reaction mixture was stirred at rt overnight. Thereaction mixture was concentrated to dryness to give the title compound(73 mg, 90%), was used in next step without further purification. MS(ESI): mass calcd. for C₁₀H₂₀N₂O₂, 200.2; m/z found, 201.2 [M+H]⁺.

Intermediate 51: 3-Methyl-5-phenoxy-pyrazin-2-amine

A solution of 5-bromo-3-methyl-pyrazin-2-amine (1000 mg, 5.32 mmol),phenol (650 mg, 6.91 mmol), Cs₂CO₃ (2600 mg, 7.98 mmol), CuI (203 mg,1.06 mmol), and N,N-dimethylglycine (110 mg, 1.06 mmol) in dioxane (5mL) was degassed and heated to 90° C. under N₂ for 12 h. After coolingto room temperature, the mixture was diluted with EtOAc (100 mL) andwater (100 mL) and the organic phase collected. The aqueous layer wasextracted again with EtOAc (100 mL) and the combined organic layers weredried over anhydrous MgSO₄ and concentrated to dryness. The residue waspurified by flash column chromatography to give the title compound as ayellow oil (533 mg, 49.8% yield). MS (ESI): mass calcd. for C₁₁H₁₁N₃O,201.1; m/z found, 202.1 [M+H]⁺.

Intermediate 52: (E)-4-(tert-Butoxycarbonylamino)-2-fluoro-but-2-enoicacid

Step A: Ethyl (E)-4-((tert-Butoxycarbonyl)amino)-2-fluorobut-2-enoate

A solution of ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (500 mg, 2.07mmol) in THF (5 mL) was cooled to 0° C. in ice-batch and NaH (60%, 50.0mg, 2.07 mmol) was added and was stirred for 30 min. tert-Butyl(2-oxoethyl)carbamate was added to the reaction mixture slowly and thereaction mixture was allowed to warm to room temperature and stirred for2 h. The reaction was worked up with DCM and water. The organic layerwas washed with brine, dried over anhydrous MgSO₄, and concentrated todryness to give the title compound.

Step B: (E)-4-(tert-Butoxycarbonylamino)-2-fluoro-but-2-enoic acid

The intermediate ethyl(E)-4-((tert-butoxycarbonyl)amino)-2-fluorobut-2-enoate was dissolved indioxane (5 mL) and water (5 mL), and NaOH was added and was reacted for10 min. The mixture was acidified with 2 M HCl to pH˜2 and extractedwith DCM. The organics were washed with brine, dried over anhydrousMgSO₄, and concentrated to dryness to give the title compound as a whitesolid (210 mg, 46% yield).

Intermediate 53: (Z)-4-(tert-Butoxycarbonylamino)-2-chloro-but-2-enoicacid

Step A: Ethyl (Z)-4-(tert-butoxycarbonylamino)-2-chloro-but-2-enoate

A solution of NaH (60%, 0.186 g, 7.73 mmol) and THF (15 mL) was cooledto 0° C. and ethyl 2-chloro-2-diethoxyphosphoryl-acetate (1.0 g, 3.9mmol) was added drop wise and stirred at 0° C. for 1 h. Then tert-butylN-(2-oxoethyl)carbamate (0.615 g, 3.87 mmol) was added dropwise andstirred at 0° C. for 1 h. The mixture was quenched with saturatedaqueous NH₄Cl, extracted with EtOAc, washed with brine, dried overanhydrous Na₂SO₄, and concentrated to dryness to give the title compoundas yellow liquid (0.59 g, 58%).

Step B: (Z)-4-(tert-Butoxycarbonylamino)-2-chloro-but-2-enoic acid

To a solution of ethyl(Z)-4-(tert-butoxycarbonylamino)-2-chloro-but-2-enoate (0.590 g, 2.24mmol) in dioxane (10 mL) and H₂O (10 mL) was added KOH (0.628 g, 11.2mmol) and the mixture was stirred at 60° C. for 2 h. Then the pH of themixture was adjusted to about 2, extracted with EtOAc, dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness to give thetitle compound as a light yellow solid (0.37 g, 70% yield), which wasused in the next step directly.

Intermediate 54:4-Oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using Method 1, steps C-F in Example 1,using o-toluidine in place of 2-methyl-4-phenoxyaniline in step C. MS(ESI): mass calcd. for C₁₆H₁₁N₃O₃S, 325.1; m/z found, 326.0 [M+H]⁺.

Intermediate 55:5-(4-Methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using Method 1, steps C-F, in Example 1,using 4-methoxy-2-methylaniline in place of 2-methyl-4-phenoxyaniline instep C. MS (ESI): mass calcd. for C₁₇H₁₃N₃O₄S, 355.1; m/z found, 356.0[M+H]⁺.

Intermediate 56:2-Amino-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

Step A: tert-Butyl(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)carbamate

5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 16) (200 mg, 0.479 mmol) was heated under reflux inredistilled thionyl chloride (0.50 mL) for 5 h. The thionyl chloride wasremoved under reduced pressure and the residue was taken up in dryacetone (2 mL), cooled to 0° C., and sodium azide (500 mg, 7.69 mmol)was added dropwise with stirring and the solution was allowed to warm to20° C. over 10 min. The reaction was diluted with water, extracted withEtOAc, and the solvent was removed under reduced pressure. The residuewas taken up into t-butyl alcohol (37.5 mL) and was heated at reflux for5 h. The reaction was concentrated to dryness to give the title compound(180 mg, 53.9% yield). MS (ESI): mass calcd. for C₂₆H₂₄N₄O₄S, 488.56;m/z found, 489.0 [M+H]⁺.

Step B:2-Amino-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

To a solution of tert-butyl(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)carbamate(180 mg, 0.258 mmol) in DCM (10 mL) were added 2,6-lutidine (166 mg,1.55 mmol) and trimethylsilyl trifluoromethanesulfonate (344 mg, 1.55mmol) and was stirred at 20° C. for 2 h. The reaction was quenched bythe addition of NaHCO₃ in ice water. The organic layer was separated andthe aqueous layer was extracted with ethyl acetate (2×50 mL). Theorganic layers were combined, washed with brine, dried over anhydrousMgSO₄, filtered, and concentrated to dryness. The residue was purifiedby preparative HPLC (column: YMC-Actus Triart C18 150×30 mm, 5 μm,mobile phase A: water (0.075% TFA (aq.), V/V; B: acetonitrile, B in Afrom 35% to 65%, flow rate: 35 mL/min) to give the title compound (40mg, 28% yield). MS (ESI): mass calcd. for C₂₁H₁₆N₄O₂S, 388.1; m/z found,389.1 [M+H]⁺.

Intermediate 57:5-(3-Bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using Method 1, steps C-F in Example 1,and using 3-bromoaniline in place of 2-methyl-4-phenoxy-aniline in stepC. MS (ESI): mass calcd. for C₁₅H₈BrN₃O₃S, 388.9; m/z found, 390.2[M+H]+.

Intermediate 58:4-Oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using Method 1, steps A-F in Example 1,using 4-fluoronitrobenzene in place of 5-fluoro-2-nitrotoluene in stepA. MS (ESI): mass calcd. for C₂₁H₁₃N₃O₄S, 403.1; m/z found, 404.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d6): δ 8.36 (d, J=5.5 Hz, 1H), 7.52-7.42(m, 4H), 7.25-7.11 (m, 6H), 6.09 (d, J=5.5 Hz, 1H).

Intermediate 59:4-Oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using Method 1, steps C-F, in Example 1,using 3-phenoxyaniline in place of 2-methyl-4-phenoxyaniline in step C.MS (ESI): mass calcd. for C₂₁H₁₃N₃O₄S, 403.1; m/z found, 404.1 [M+H]⁺.

Intermediate 60:4-Oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

Step A: 2-Nitro-5-phenoxypyridine

A round bottom flask containing 5-bromo-2-nitropyridine (300 g, 1480mmol) and DMSO (1200 mL) was treated with phenol (167 g, 1770 mmol)followed by Cs₂CO₃ (722 g, 2220 mmol). The reaction mixture was stirredat 50° C. for 4 h. The mixture was transferred to a flask containingice-water (5 L). The resulting precipitate was collected by filtration,rinsed with water, and dried at 70° C. under vacuum to yield the titlecompound (230 g, 72% yield) as a grey solid. MS (ESI): mass calcd. forC₁₁H₈N₂O₃, 216.05; m/z found, 217.0 [M+H]⁺.

Step B: 5-Phenoxypyridin-2-amine

To a solution of 2-nitro-5-phenoxypyridine (100 g, 463 mmol) in MeOH(1.5 L) was added 10% Pd-C (10 g). The reaction mixture was stirredunder an atmosphere of H₂ at room temperature for 24 hours. The mixturewas filtered, and the filtrate was concentrated to dryness under vacuoto yield the title compound (85 g, 99% yield) as a yellow solid. MS(ESI): mass calcd. for C₁₁H₁₀N₂O, 186.08; m/z found, 187.1 [M+H]⁺.

Step C: Methyl3-amino-4-((5-phenoxypyridin-2-yl)amino)thieno[2,3-b]pyridine-2-carboxylate

To a round bottom flask containing2-chloro-4-iodopyridine-3-carbonitrile (148 g, 559 mmol) and5-phenoxypyridin-2-amine (80.0 g, 430 mmol) were added Pd(OAc)₂ (9.62 g,43.0 mmol), followed by bis(2-diphenylphosphinophenyl)ether (DPEphos,46.2 g, 85.9 mmol), and cesium carbonate (350.0 g, 107.0 mmol). Thereaction mixture was treated with 1,4-dioxane (2 L), the vessel waspurged with N₂, then stirred at 105° C. for 3 h. Methyl2-sulfanylacetate (68.4 g, 644 mmol) was added, and the reaction washeated for an additional 16 h at 105° C. The reaction mixture wasfiltered, the filtrate was concentrated to dryness, and the residue wastreated with MeOH (800 mL). The resulting solid was isolated byfiltration and dried under vacuum to give the title compound (130 g,77%) as a yellow solid. MS (ESI): mass calcd. for C₂₀H₁₆N₄O₃S, 392.09;m/z found, 393.2 [M+H]⁺.

Step D: Methyl4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

To a round bottom flask were added methyl3-amino-4-((5-phenoxypyridin-2-yl)amino)thieno[2,3-b]pyridine-2-carboxylate(28.3 g, 72.1 mmol), carbonyldiimidazole (58.5 g, 361 mmol), and1,4-dioxane (200 ml). The reaction was heated at reflux for 16 h. Thenthe reaction mixture was concentrated to dryness and the residue wastreated with MeOH (200 mL). The resulting precipitate was isolated byfiltration, rinsed with cold MeOH, and dried under vacuum to yield thetitle compound (21.0 g, 70% yield) as a yellow solid. MS (ESI): masscalcd. for C₂₁H₁₄N₄O₄S, 418.07; m/z found, 419.0 [M+H]⁺.

Step E:4-Oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

To a round bottom flask were added methyl4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(20.0 g, 47.8 mmol), lithium hydroxide (20.0 g, 476 mmol), THF (250 mL),MeOH (100 mL), and water (100 mL). The reaction mixture was stirred at80° C. for 4 h. The mixture was concentrated to dryness and diluted withH₂O (100 mL). The pH was adjusted to 1 with 1 M HCl and the precipitatewas filtered and dried to yield the title compound (18.0 g, 93% yield)as yellow solid. MS (ESI): mass calcd. for C₂₀H₁₂N₄O₄S, 404.06; m/zfound, 405.0 [M+H]⁺.

Intermediate 61:4-Oxo-N-(piperidin-3-yl)-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using Method 1, step G-H in Example 1,using using4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 54) and tert-butyl-3-aminopiperidine-1-carboxylate inplace of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid and tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate. MS(ESI): mass calcd. for C₂₁H₂₁N₅O₂S, 407.1; m/z found, 408.1 [M+H]⁺.

Intermediate 62:5-(2-Methyl-3-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using Method 1, steps A-F, in Example 1,using 1-bromo-2-methyl-3-nitrobenzene in place of4-fluoro-2-methyl-1-nitrobenzene in step A. MS (ESI): mass calcd. forC₂₂H₁₅N₃O₄S, 417.1; m/z found, 418.0 [M+H]⁺.

Intermediate 63:(*R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using Method 1, steps A-F in Example 1(including Chiral resolution Method A after Step F to obtain the *Ratropisomer). MS (ESI): mass calcd. for C₂₂H₁₅N₃O₄S, 417.1; m/z found,418.0 [M+H]+.

Intermediate 64:5-(2-Methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

Step A: 1-Methyl-2-nitro-4-phenoxybenzene

A mixture of 4-methyl-3-nitrophenol (3.06 g, 20 mmol), phenylboronicacid (4.88 g, 40 mmol), Cu(AcO)₂ (5.20 g, 40 mmol) and 4 A MS (1.5 g) inDCM was stirred at rt under oxygen overnight, then the reaction wasfiltrated and concentrated. The crude was purified using with ISCOeluting with PE/EA to give the title compound (3.16 g, 67%).

Step B:5-(2-Methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using Method 1, steps B-F, in Example 1,using 1-methyl-2-nitro-4-phenoxybenzene in place of2-methyl-1-nitro-4-phenoxybenzene in step B. MS (ESI): mass calcd. forC₂₂H₁₅N₃O₄S, 417.1; m/z found, 418.0 [M+H]⁺.

Intermediate 65:5-(2-Fluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using conditions analogous toIntermediate 64, steps A-B, using 3-fluoro-4-nitrophenol in place of4-methyl-3-nitrophenol. MS (ESI): mass calcd. for C₂₁H₁₂FN₃O₄S, 421.1;m/z found, 422.0 [M+H]+.

Intermediate 66:5-(4-Methoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using Method 1, step G in Example 1, andusing5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 55) and tert-butyl-3-aminopiperidine-1-carboxylate inplace of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid and tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate. MS(ESI): mass calcd. for C₂₂H₂₃N₅O₃S, 437.2; m/z found, 438.1 [M+H]⁺.

Intermediate 67:5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

Step A: Methyl5-(4-bromo-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

The title compound was prepared using Method 1, steps C-E, in Example 1,using 4-bromo-2-methylaniline in place of 2-methyl-4-phenoxyaniline instep C as a yellow solid.

Step B: Methyl5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

The mixture of methyl5-(4-bromo-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(1.0 g, 2.2 mmol), 2-methoxyphenol (1.1 g, 8.9 mmol), Cs₂CO₃ (1.4 g, 4.4mmol), CuCl (44 mg, 0.44 mmol), quinolin-8-ol (64 mg, 0.44 mmol) in NMP(10 mL) was stirred at 165° C. in sealed tube for 35 minutes. Then waspurified by flash column chromatography eluting with PE/EA to yield thetitle compound (634 mg, 62% yield) as a grey solid.

Step C:5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using Method 1, step F, in Example 1,using methyl5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylatein place of methyl5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylateas a grey solid. MS (ESI): mass calcd. for C₂₃H₁₇N₃O₅S, 447.1; m/zfound, 448.0 [M+H]⁺.

Intermediate 68: Methyl5-(3-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

Step A: 3-Chloro-4-phenoxyaniline

The title compound was prepared using analogous conditions described inMethod 1, steps A-B in Example 1, and using2-chloro-1-fluoro-4-nitrobenzene in place of 5-fluoro-2-nitrotoluene instep A, to give the title compound. MS (ESI): mass calcd. forC₁₂H₁₀ClNO, 219.67; m/z found, 220.1 [M+H]⁺.

Step B: Methyl5-(3-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

The title compound was prepared using analogous conditions described inExample 534, step A, and using 3-chloro-4-phenoxyaniline and methyl2-sulfanylacetate in place of 3-cyclobutylaniline and tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate22), to give the title compound. MS (ESI): mass calcd. for C₁₂H₁₀ClNO,219.0; m/z found, 220.1 [M+H]⁺.

Intermediate 69:5-(4-Methoxybenzyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using Method 1, steps C-F in Example 1,using (4-methoxyphenyl)methanamine in place of 2-methyl-4-phenoxyanilineand DIPEA in place of Cs₂CO₃, Pd(AcO)₂ and DPEphos in step C. MS (ESI):mass calcd. for C₁₇H₁₃N₃O₄S, 355.1; m/z found, 356.0 [M+H]⁺.

Intermediate 70:(R)-5-(4-Isopropoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using Method 1, steps B-H in Example 1,and using 4-isopropoxy-2-methyl-1-nitrobenzene in place of2-methyl-1-nitro-4-phenoxybenzene in step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₄H₂₇N₅O₃S, 465.2; m/z found, 466.2 [M+H]⁺.

Intermediate 71:(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using Method 1, step G-H, in Example 1,using tert-butyl (S)-3-aminopyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate in step G.MS (ESI): mass calcd. for C₂₆H₂₃N₅O₃S, 485.2; m/z found, 486.5 [M+H]⁺.

Intermediate 72:(E)-4-((4aR,7aS)-Hexahydro-6H-[1,4]dioxino[2,3-c]pyrrol-6-yl)but-2-enoicacid

Step A: Benzyl 3,4-dihydroxypyrrolidine-1-carboxylate

Benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (5.0 g, 25 mmol) was takenup in THF (40 mL) and water (15 mL) and to this solution were added OsO₄(63 mg, 0.25 mmol) and 4-methylmorpholine 4-oxide (3.75 g, 32.0 mmol).The reaction was stirred at room temperature for 15 h. The reaction wasconcentrated to dryness and the crude was partitioned between EtOAc andwater. The layers were separated and the aqueous layer was extractedwith EtOAc. The combined organic layers were dried over anhydrousNa₂SO₄, concentrated to dryness, and purified by normal phase flashcolumn chromatography (SiO₂) to give the title compound (4.8 g, 82%yield). MS (ESI): mass calcd. for C₁₂H₁₅NO₄, 237.25; m/z found, 238.1[M+H]⁺.

Step B: (4aR,7aS)-Benzyltetrahydro-2H-[1,4]dioxino[2,3-c]pyrrole-6(3H)-carboxylate

To a solution of NaOH (9.00 g, 225 mmol) in water (30 mL) were addedbenzyl 3,4-dihydroxypyrrolidine-1-carboxylate (4.8 g, 20 mmol), anddichloroethane (30 mL). To this solution was added tetrabutylammoniumfluoride (2.65 g, 10.1 mmol) and the mixture was stirred at 55° C. for48 h. The mixture was extracted with DCM, concentrated to dryness, andpurified by normal phase flash column chromatography (SiO₂) to give thetitle compound as a white solid (0.96 g, 18% yield). MS (ESI): masscalcd. for C₁₄H₁₇NO₄, 263.29; m/z found, 264.1 [M+H]⁺.

Step C: (4aR,7aS)-3,4a,5,6,7,7a-Hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole

A solution of (4aR,7aS)-benzyltetrahydro-2H-[1,4]dioxino[2,3-c]pyrrole-6(3H)-carboxylate (0.96 g, 3.6mmol), Pd(OH)₂ (51 mg, 0.36 mmol), and MeOH (10 mL) were reacted at roomtemperature for 3 h under H₂. The mixture was filtered and concentratedto dryness to give the title compound as a light yellow solid (0.43 g,91% yield). MS (ESI): mass calcd. for C₆H₁₁NO₂, 129.16; m/z found, 130.4[M+H]⁺.

Step D: (E)-Methyl4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoate

To a solution of methyl (E)-4-bromobut-2-enoate (42 mg, 0.23 mmol) anddiisopropylethylamine (30 mg, 0.23 mmol) in THF (10 mL) was added(4aR,7aS)-3,4a,5,6,7,7a-hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (30 mg,0.23 mmol), and was stirred at room temperature for 15 h. The mixturewas concentrated to dryness to give the title compound (55 mg), whichwas used in the next step without further purification. MS (ESI): masscalcd. for C₁₁H₁₇NO₄, 227.26; m/z found, 228.1 [M+H]⁺.

Step E:(E)-4-((4aR,7aS)-Tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoicacid

A solution of (E)-methyl4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoate(55 mg, 0.24 mmol) and aqueous 4 M HCl (5 mL) was reacted at reflux for1 h. The mixture was concentrated to dryness to give the title compound(55 mg, 106%), which was used without further purification.

Intermediate 73: Methyl5-(2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

Step A: 3-Methyl-4-nitro-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide

To a solution of 3-methyl-4-nitrobenzoic acid (3.0 g, 16.6 mmol) in DCM(100 mL) was added one drop of DMF and oxalyl dichloride (10.5 g, 82.8mmol). The mixture was stirred at room temperature for 30 minutes, thenconcentrated and diluted in DCM, then added to a solution of4-(trifluoromethyl)pyridin-2-amine (2.7 g, 16.6 mmol), triethylamine inDCM under ice-bath, stirred for 1 hour. The mixture was concentrated toyield the title compound as a yellow solid, which was used forward nextstep without further purification.

Step B: Methyl5-(2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

The title compound was prepared using Method 1, steps B-E, in Example 1,using 3-methyl-4-nitro-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide inplace of 2-methyl-1-nitro-4-phenoxybenzene in step B.

Intermediate 74: Methyl5-(2-fluoro-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

Step A: 3-Fluoro-4-nitro-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide

To the suspension of 3-fluoro-4-nitrobenzoic acid acid (4.1 g, 22.1mmol) in 30 ml of DCM was added Oxalyl chloride (3.0 g, 24.4 mmol) and 1drop of DMF, then was stirred at room temperature for 4 hours. Afterconcentration under vacuo to dryness, the residue was dissolved in 10 mlof DCM and was added a solution of 4-(trifluoromethyl)pyridin-2-amine(3.6 g, 22.1 mmol) in 30 ml of DCM, stirred at room temperature for 5mins. The mixture was concentrated and purified by ISCO using MeOH/H₂Oas eluent to get the title compound as yellow solid acid (5.0 g, 69%yield).

Step B: Methyl5-(2-fluoro-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

The title compound was prepared using Method 1, steps B-E in Example 1,using 3-fluoro-4-nitro-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide inplace of 2-methyl-1-nitro-4-phenoxybenzene in step B.

Intermediate 75:5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using Method 1, step F in Example 1,using methyl5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(Intermediate 76) in place of methyl5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate.MS (ESI): mass calcd. for C₃₀H₂₀N₄O₅S, 548.1; m/z found, 549.0 [M+H]⁺.

Intermediate 76: Methyl5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

Step A: 3-((tert-Butldimethylsilyl)oxy)benzaldehyde

To a mixture of 3-hydroxybenzaldehyde (24.4 g, 200 mmol) in DCM (500 mL)was added Et₃N (30.3 g, 300 mmol) and TBSCl (33.1 g, 220 mmol) andstirred room temperature for 3 hours. The reaction was dispersed betweenDCM and saturated NH₄Cl aq solution. The organic layer was collected,condensed and was purified by flash column chromatography (PE/EA) togive the title compound (47.3 g, 100% yield). ¹H NMR (400 MHz, DMSO-d6):δ ppm 10.01 (s, 1H), 7.50-7.63 (m, 2H), 7.37 (s, 1H), 7.25 (d, J=7.50Hz, 1H), 1.01 (s, 9H), 0.26 (s, 6H)

Step B: (3-((tert-Butyldimethylsilyl)oxy)phenyl)methanol

To a mixture of 3-((tert-butyldimethylsilyl)oxy)benzaldehyde (47.3 g,200 mmol) in MeOH (30 mL) cooled to 0° C. was added portion wise NaBH₄(3.78 g, 100 mmol). After the addition was completed the reaction wasstirred at room temperature for 2 hours. Volatiles were removed undervacuo. Water and EtOAc were added to the residue, the organic layer wasseparated, washed with brine, dried over Na₂SO₄, filtered andconcentrated under vacuo to provide target product as yellow oil, whichwas used forward next step without further purification. Mass calcd. forC₁₃H₂₂O₂Si, 238.1. ¹H NMR (400 MHz, DMSO-d6): δ ppm 0.18-0.27 (m, 6H)0.99 (s, 9H) 4.48 (s, 2H) 5.23 (br. s., 1H) 6.69-6.78 (m, 1H) 6.85 (s,1H) 6.93 (d, J=7.50 Hz, 1H) 7.23 (t, J=7.94 Hz, 1H).

Step C: 2-((3-((tert-Butyldimethylsilyl)oxy)benzyl)oxy)benzonitrile

To a mixture of (3-((tert-butyldimethylsilyl)oxy)phenyl)methanol (13.94g, 60 mmol) in THF (200 mL) were sequentially added2-hydroxybenzonitrile (8.58 g, 72 mmol), Ph₃P (18.88 g, 72 mmol) andDIAD (14.56 g, 72 mmol): dropwise at room temperature and the reactionwas stirred for 1 hour. Saturated aqueous NH₄Cl and EtOAc were added,the organic layer was separated, washed with brine, dried over Na₂SO₄,filtered, condensed under vacuo and was purified by flash columnchromatography (PE/EA) to give the title compound (17.0 g, 83% yield).

Step D: 2-((3-Hydroxybenzyl)oxy)benzonitrile

To a mixture of2-((3-((tert-butyldimethylsilyl)oxy)benzyl)oxy)benzonitrile (17.0 g, 50mmol) in THF (250 mL) was added a 1M solution TBAF (60 mL, 60 mmol) andthe reaction was stirred at room temperature for 30 minutes. A saturatedaqueous NH₄Cl solution and EtOAc were added, the organic layer wasseparated, washed with brine, dried over Na₂SO₄, filtered, condensed andwas purified by flash column chromatography(MeOH/DCM) to give the titlecompound (11.3 g, 100% yield).

Step E: 2-((3-(3-Methyl-4-nitrophenoxy)benzyl)oxy)benzonitrile

To a mixture of 2-((3-hydroxybenzyl)oxy)benzonitrile (11.3 g, 50 mmol),4-fluoro-2-methyl-1-nitrobenzene (7.8 g, 50 mmol), K₂CO₃ (13.8 g, 100mmol) in 200 mL of DMSO was stirred under N₂ at 150° C. for 4 hours. Themixture was condensed and was purified by flash column chromatography(PE/EA) to give the title compound (15.1 g, 84% yield). MS (ESI): masscalcd. for C₂₁H₁₆N₂O₄, 360.1; m/z found, 361.0 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ 8.11-7.98 (m, 1H), 7.74-7.62 (m, 1H), 7.62-7.39 (m, 6H),7.39-7.31 (m, 1H), 7.22-7.17 (m, 1H), 7.09-6.97 (m, 3H), 6.85 (d, J=8.4Hz, 2H), 6.55 (s, 1H), 5.21 (s, 2H), 2.58 (s, 3H).

Step F: 2-((3-(4-Amino-3-methylphenoxy)benzyl)oxy)benzonitrile

To a mixture of 2-((3-(3-methyl-4-nitrophenoxy)benzyl)oxy)benzonitrile(15.1 g, 42 mmol) in EtOH (420 mL) and water (140 mL) were sequentiallyadded NH₄Cl (11.2 g, 210 mmol), iron (9.38 g, 168 mmol) and the reactionmixture was stirred at reflux for 4 hours and then cooled to roomtemperature, The mixture was diluted with DCM (500 mL) and water (200mL), the organic layer was collected, condensed and was purified byflash column chromatography (MeOH/water) to give the title compound(13.9 g, 100% yield). MS (ESI): mass calcd. for C₂₁H₁₈N₂O₂, 330.1; m/zfound, 331.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.57 (dd, J=7.6, 1.7 Hz,1H), 7.53-7.45 (m, 1H), 7.33-7.24 (m, 1H), 7.15-7.08 (m, 1H), 7.04-6.84(m, 5H), 6.82-6.72 (m, 2H), 6.67 (d, J=8.4 Hz, 1H), 5.14 (s, 2H), 2.15(s, 3H).

Step G: Methyl5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

The title compound was prepared using Method 1, steps C-E in Example 1,using 2-((3-(4-amino-3-methylphenoxy)benzyl)oxy)benzonitrile in place of2-methyl-4-phenoxyaniline in step C. MS (ESI): mass calcd. forC₃₁H₂₂N₄O₅S, 562.1; m/z found, 563.2 [M+H]⁺.

Intermediate 77:(R)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 711) (3.4 g, 6.8 mmol) in DCM (50 mL) was added triethylamine(2.06 g, 20.4 mmol) and was cooled to 0° C. Next2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (1.86 g, 10.2 mmol) was addedslowly and after the addition was complete, it was stirred at roomtemperature for 1 h. The reaction was washed with 1% HCl, NaHCO₃, andbrine, dried over anhydrous Na₂SO₄, and concentrated to dryness. Theresidue was washed with DCM, the solid was collected by filtration anddried in a vacuum to give the title compound (3.0 g, 58% yield) as ayellow solid. MS (ESI): mass calcd. for C₂₉H₂₅N₇O₄S, 567.62; m/z found,568.1 [M+H]⁺.

Intermediate 78:(R)-5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using Method 1, step G-H in Example 1,and using5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 75) and tert-butyl(R)-3-aminopiperidine-1-carboxylate in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid and tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate. MS(ESI): mass calcd. for C₃5H30N6O4S, 630.2; m/z found, 631.0 [M+H]⁺.

Intermediate 79: 1-Acryloylpiperidin-3-one

A solution of tert-butyl 3-oxopiperidine-1-carboxylate (1.00 g, 5.0mmol) in 6 M HCl in MeOH (25 mL) was stirred at rt for 30 min, thenconcentrated to dryness. The residue was diluted in acetone/water (50mL), and triethylamine (1.02 g, 10.0 mmol) and K₂CO₃ (1.39 g, 10.0 mmol)were added, followed by addition of prop-2-enoyl chloride (454 mg, 5.0mmol). The mixture was stirred at rt for 18 h, extracted with EtOAc, theorganic layers washed with water and brine, dried over anhydrous Na₂SO₄,and concentrated to dryness. The residue was purified by flash columnchromatography to give the title compound as a white solid (480 mg, 62%yield). MS (ESI): mass calcd. for C₈H11NO2, 153.1; m/z found, 154.1[M+H]⁺.

Intermediate 80: 1-Acryloylpiperidin-4-one

A solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.5 g, 7.5 mmol)in 6 M HCl in MeOH (25 mL) was stirred at rt for 30 min, thenconcentrated to dryness. The residue was diluted in acetone/water (30mL), and triethylamine (2.28 g, 22.6 mmol) and K₂CO₃ (2.08 g, 15.1 mmol)were added, followed by the addition of prop-2-enoyl chloride (681 mg,7.53 mmol). The mixture was stirred at rt for 18 h, then extracted withEtOAc and the organic layers were washed with water and brine, driedover anhydrous Na₂SO₄, and concentrated to dryness. The residue waspurified by flash column chromatography to give the title compound as awhite solid (500 mg, 43%). MS (ESI): mass calcd. for C₈H11NO2, 153.1;m/z found, 154.1 [M+H]⁺.

Intermediate 81:5-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

Step A: 6-Isobutyl-4-methylpyridin-3-amine

To a 200 mL round bottom flask was were added6-bromo-4-methylpyridin-3-amine (5.42 g, 29.0 mmol), a stir bar, and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (520 mg, 0.6 mmol). The vessel was evacuatedthen back filled with nitrogen. THF (20 mL) was added, followed byisobutylzinc(II) bromide (80 mL, 40 mmol) via syringe, then the reactionmixture was heated to 60° C. for 2 h. The reaction mixture was treatedwith saturated aqueous sodium bicarbonate (300 mL) and extracted withEtOAc (2×300 mL). The combined organic layers were dried (MgSO₄),concentrated to dryness, and the residue purified by flash columnchromatography to give the title compound (3.65 g, 77% yield) as a brownsolid. MS (ESI): mass calcd. for C₁₀H₁₆N₂, 164.1; m/z found, 165.1[M+H]⁺.

Step B: Methyl3-amino-4-((6-isobutyl-4-methylpyridin-3-yl)amino)thieno[2,3-b]pyridine-2-carboxylate

To a round bottom flask under a N₂ atmosphere were added6-isobutyl-4-methylpyridin-3-amine (53.5 g, 326 mmol),2-chloro-4-iodopyridine-3-carbonitrile (94.8 g, 358 mmol), and dioxane(1000 mL), followed by bis(2-diphenylphosphinophenyl)ether (DPEphos)(10.5 g, 19.5 mmol), Pd(OAc)₂ (2.92 g, 13.0 mmol), and Cs₂CO₃ (265 g,814 mmol). The reaction mixture was stirred at 105° C. overnight. Thereaction mixture was filtered and concentrated. The residue wassuspended in MeOH (400 mL) and stirred for 2 h at room temperature. Theresulting precipitate was isolated by filtration and dried under vacuumto give the title compound (75.3 g, 62% yield) as a yellow solid.

Step C: Methyl5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

To a round bottom flask were added Methyl3-amino-4-((6-isobutyl-4-methylpyridin-3-yl)amino)thieno[2,3-b]pyridine-2-carboxylate(30.0 g, 81 mmol), carbonyldiimidazole (CDI, 39.4 g, 243 mmol),trimethylamine (24.6 g, 243 mmol) and 1,4-dioxane (300 mL). The reactionwas stirred at 100° C. for 6 h, then cooled to 50° C. The resultingprecipitate was collected by filtration, rinsed with MeOH and driedunder vacuum to yield the title compound (27 g, 84%) as an off-whitesolid.

Step D:5-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

To a round bottom flask were added methyl5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(68.0 g, 172 mmol), lithium hydroxide (36.0 g, 858 mmol), and a mixtureof 5:2:2 THF:MeOH:H₂O (4 L). The reaction mixture was stirred at 80° C.for 4.5 h. The mixture was concentrated to dryness and diluted with H₂O.The solution was acidified by the addition of 1 M HCl and the resultingprecipitate was filtered and dried under vacuum to yield the titlecompound (63 g, 96% yield) as yellow solid. MS (ESI): mass calcd. forC₁₉H₁₈N₄O₃S, 382.11; m/z found, 383.1 [M+H]⁺.

Intermediate 82:5-(*S)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

5-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 81) was resolved using Chiral resolution Method B toobtain the title compound (*S atropisomer). MS (ESI): mass calcd. forC₁₉H₁₈N₄O₃S, 382.1; m/z found, 383.0 [M+H]⁺.

Intermediate 83:5-(*R)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

5-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 81) was resolved using Chiral resolution Method B toobtain the title compound (*R atropisomer). MS (ESI): mass calcd. forC₁₉H₁₈N₄O₃S, 382.1; m/z found, 383.0 [M+H]⁺.

Example 1:N-((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Method 1. Step A: 2-Methyl-1-nitro-4-phenoxybenzene

To a round bottom flask were added phenol (42.5 g, 452 mmol), K₂CO₃ (125g, 905 mmol), and DMF (500 mL). To the reaction mixture was added5-fluoro-2-nitrotoluene (70.2 g, 452 mmol) and the reaction was stirredat 80° C. for 16 h under N2. The reaction was diluted with saturatedNH₄Cl and extracted with MTBE (3×400 mL). The organic layers werecombined, dried over anhydrous Na₂SO₄, filtered, and concentrated todryness to yield the title compound (100 g, 92% yield) as a brown oil.

Method 1, Step B: 2-Methyl-4-phenoxyaniline

To a solution of 2-methyl-1-nitro-4-phenoxybenzene (100 g, 436 mmol) inEtOH/H₂O (3:1 ratio, 2000 mL) were sequentially added NH₄Cl (117 g, 2180mmol) and Fe (97 g, 1700 mmol). The reaction mixture was heated toreflux for 2 h, then the reaction was cooled to 25° C. and concentratedto dryness. To the residue was added water and EtOAc and the organiclayer was separated, washed with saturated NaHCO₃ and saturated brine,dried over anhydrous MgSO₄, filtered, and concentrated to dryness toyield the title compound (82 g, 90% yield).

Method 1, Step C:2-Chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrile

To a round bottom flask under a N₂ atmosphere were added2-methyl-4-phenoxyaniline (30 g, 150 mmol),2-chloro-4-iodopyridine-3-carbonitrile (51.6 g, 195 mmol), and dioxane(200 mL), followed by bis(2-diphenylphosphinophenyl)ether (DPEphos) (16g, 30 mmol), Pd(OAc)₂ (3.36 g, 15 mmol), and K₃PO₄ (89 g, 420 mmol). Thereaction mixture was stirred at 100° C. overnight. The reaction mixturewas filtered and purified flash column chromatography to yield the titlecompound (32 g, 63% yield) as a yellow solid.

Method 1, Step D: Methyl3-amino-4-(2-methyl-4-phenoxyanilino)thieno[2,3-b]pyridine-2-carboxylate

To a round bottom flask were added2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrile (36 g, 107mmol) in MeOH (150 mL). To this solution was added NaOMe (14.5 g, 268mmol) in MeOH (30 mL), followed by methyl 2-sulfanylacetate (23 g, 217mmol). The reaction mixture was refluxed overnight. The reaction mixturewas cooled and the yellow precipitate was filtered off, washed withMeOH, and dried to yield the title compound (30 g, 75% yield) as ayellow solid.

Method 1, Step E: Methyl5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

To a round bottom flask were added methyl3-amino-4-(2-methyl-4-phenoxyanilino)thieno[2,3-b]pyridine-2-carboxylate(30.6 g, 75.5 mmol), carbonyldiimidazole (CDI, 49 g, 300 mmol), and1,4-dioxane (500 ml). The reaction was stirred at reflux overnight. Thenthe reaction mixture was concentrated to dryness and to the residue wasadded to MeOH (200 mL) and the precipitate that formed was filtered offand dried to yield the title compound (28.1 g, 86% yield) as a yellowsolid.

Method 1, Step F:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

To a round bottom flask were added Methyl5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(9.2 g, 21 mmol), lithium hydroxide (4.47 g, 106 mmol), THF (200 mL),MeOH (200 mL), and water (50 mL). The reaction mixture was stirred at50° C. for 15 h. The mixture was concentrated to dryness and dilutedwith H₂O. The pH was adjusted to 2 with 1 M aqueous HCl and theprecipitate was filtered and dried to yield the title compound (8.1 g,91% yield) as yellow solid.

Method 1, Step G: tert-Butyl(3R,5R)-3-fluoro-5-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,58-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a round bottom flask were added5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27, 191 mg, 0.458 mmol), tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1, 100mg, 0.458 mmol), triethylamine (93 mg, 0.916 mmol), HATU (348 mg, 0.916mmol), and DMF (3 mL). The reaction mixture was stirred at rt for 3 h.Water was added and the precipitate was collected by filtration to yielda pale yellow solid.

Method 1, Step H:N-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

tert-Butyl(3R,5R)-3-fluoro-5-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylatewas dissolved in MeOH (3 mL) and saturated aqueous HCl (3 mL) was added.The resulting mixture was heated to 50° C. for 30 min. The reactionmixture was concentrated to dryness and the residue was purified byflash column chromatography to yield the title compound (Example 138, 80mg, 31% yield over 2 steps) as a yellow solid.

Method 1, Step I:N-((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were addedN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 138, 40 mg, 0.077 mmol), triethylamine (23 mg, 0.054 mmol), andDCM (3 mL). Next, prop-2-enoyl chloride (5.0 mg, 0.054 mmol) was addeddropwise at 0° C., then stirred at rt for 1 h. The reaction mixture wasconcentrated to dryness and the residue purified by flash columnchromatography to yield the title compound (22 mg, 48% yield) as a paleyellow solid. MS (ESI): mass calcd. for C₃₀H₂₆FN₅O₄S, 571.6; m/z found,572.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.28 (d, J=5.5 Hz, 1H),7.42-7.30 (m, 2H), 7.30-7.22 (m, 1H), 7.16-7.08 (m, 1H), 7.08-6.97 (m,3H), 6.95-6.87 (m, 1H), 6.80-6.61 (m, 1H), 6.19-6.05 (m, 1H), 5.98 (d,J=5.5 Hz, 1H), 5.72-5.60 (m, 1H), 4.82-4.57 (m, 1H), 4.17-4.05 (m, 1H),4.02-3.85 (m, 2H), 3.55-3.28 (m, 2H), 2.39-2.18 (m, 1H), 2.04 (s, 3H),2.0-1.91 (m, 1H).

Example 2:N-((3R,5S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral Resolution Step A to obtain the *S atropisomer) inExample 1, and using tert-butyl(3R,5S)-3-amino-5-hydroxypiperidine-1-carboxylate (Intermediate 2) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₅S,569.6; m/z found, 570.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.36-8.27 (m,1H), 7.45-7.37 (m, 2H), 7.33-7.26 (m, 1H), 7.21-7.14 (m, 1H), 7.11-7.02(m, 3H), 7.00-6.92 (m, 1H), 6.85-6.65 (m, 1H), 6.21-6.09 (m, 1H),6.06-6.02 (m, 1H), 5.75-5.61 (m, 1H), 4.20-3.75 (m, 4H), 3.66-3.55 (m,2H), 2.21-2.12 (m, 1H), 2.11 (s, 3H), 1.90-1.77 (m, 1H).

Example 3:N-((3R,5S)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The titled compound was prepared using Method 1, steps A-I in Example 1,and using tert-butyl (3R,5S)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 3) in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₂₆FN₅O₄S, 571.6; m/z found, 572.4[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.26 (s, 1H), 8.31 (d, J=4.7 Hz,1H), 8.26-8.00 (m, 1H), 7.57-7.29 (m, 3H), 7.29-6.91 (m, 5H), 6.88-6.65(m, 1H), 6.11 (d, J=16.7 Hz, 1H), 6.03-5.87 (m, 1H), 5.77-5.60 (m, 1H),5.15-4.85 (m, 1H), 4.70-4.47 (m, 1H), 4.35-4.38 (m, 2H), 3.06-2.61 (m,2H), 2.30-2.12 (m, 1H), 2.05 (s, 3H), 1.97-1.78 (m, 1H).

Example 4:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps B-I in Example 1, and using2-fluoro-3-methyl-4-nitro-1-phenoxybenzene (Intermediate 18, step B) inplace of 2-methyl-4-phenoxyaniline in step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₂₆FN₅O₄S, 571.6; m/z found, 572.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34 (d, J=5.4 Hz, 1H), 7.41-7.34 (m,2H), 7.22-7.11 (m, 2H), 7.10-7.04 (m, 3H), 6.84-6.72 (m, 1H), 6.19 (d,J=17.0 Hz, 1H), 6.12 (d, J=5.4 Hz, 1H), 5.76-5.69 (m, 1H), 4.56-4.48 (m,0.5H), 4.32-4.25 (m, 0.5H), 4.4.20-4.13 (m, 0.5H), 4.02-3.88 (m, 1.5H),3.22-3.12 (m, 1H), 2.95-2.83 (m, 1H), 2.12 (s, 3H), 2.07-2.00 (m, 1H),1.90-1.82 (m, 1H), 1.78-1.66 (m, 1H), 1.63-1.54 (m, 1H).

Example 5:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral resolution Method A after Step F to obtain the *Satropisomer) in Example 1, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₉H₂₅N₅O₄S, 539.6; m/z found, 540.30[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.24 (s, 1H), 8.43-8.22 (m, 2H),7.57-7.29 (m, 3H), 7.25-7.04 (m, 4H), 7.03-6.90 (m, 1H), 6.70-6.45 (m,1H), 6.13 (d, J=16.4 Hz, 1H), 6.05-6.88 (m, 1H), 5.73-5.57 (m, 1H),4.60-4.30 (m, 1H), 3.91-3.36 (m, 4H), 2.24-1.89 (m, 5H).

Example 6:N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3R,5R)-3-amino-5-hydroxypiperidine-1-carboxylate (Intermediate 4) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₅S,569.6; m/z found, 570.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34-8.18 (m,1H), 7.46-7.36 (m, 2H), 7.33-7.22 (m, 1H), 7.20-7.13 (m, 1H), 7.13-7.02(m, 3H), 7.00-6.94 (m, 1H), 6.88-6.70 (m, 1H), 6.25-6.10 (m, 1H),6.05-5.92 (m, 1H), 5.76-5.67 (m, 1H), 4.66-4.28 (m, 2H), 4.23-3.83 (m,2.5H), 3.45-3.34 (m, 1H), 3.02-2.87 (m, 0.5H), 2.12 (s, 3H), 2.09-1.88(m, 2H).

Example 7:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate 5) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₉H₂₄FN₅O₄S,557.6; m/z found, 558.4 [M+H]⁺. ¹H NMR (400 MHz, a mixture of DMSO-d₆and CD₃OD): δ 8.26 (d, J=5.5 Hz, 1H), 7.7.39-7.29 (m, 2H), 7.20-7.13 (m,1H), 7.12-6.97 (m, 4H), 6.60-6.43 (m, 1H), 6.19-6.09 (m, 1H), 6.02 (d,J=5.4 Hz, 1H), 5.66-5.58 (m, 1H), 4.55-4.42 (m, 1H), 3.89-3.80 (m, 1H),3.72-3.66 (m, 1H), 3.60-3.49 (m, 1H), 3.48-3.38 (m, 1H), 2.22-2.08 (m,1H), 2.01 (s, 3H), 1.99-1.87 (m, 1H).

Example 8:N-((3R,5R)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3R,5R)-3-amino-5-methoxypiperidine-1-carboxylate (Intermediate 6) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₁H₂₉N₅O₅S,583.7; m/z found, 584.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d,J=5.5 Hz, 1H), 7.52-7.37 (m, 2H), 7.38-7.26 (m, 1H), 7.22-7.14 (m, 1H),7.13-7.03 (m, 3H), 7.01-6.94 (m, 1H), 6.89-6.68 (m, 1H), 6.25-6.13 (m,1H), 6.07 (d, J=5.6 Hz, 1H), 5.79-5.68 (m, 1H), 4.70-4.51 (m, 1H),4.35-4.06 (m, 2H), 3.76-3.55 (m, 1H), 3.41-3.33 (m, 3H), 3.27-3.08 (m,1H), 3.02-2.69 (m, 1H), 2.33-2.10 (m, 4H), 2.07-1.74 (m, 1H).

Example 9:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral resolution Method A after Step F to obtain the *Satropisomer) in Example 1, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₄S, 553.6; m/z found, 554.40[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d, J=5.5 Hz, 1H), 7.47-7.35 (m,2H), 7.33-7.26 (m, 1H), 7.122-7.16 (m, 1H), 7.13-7.02 (m, 3H), 7.00-6.93(m, 1H), 6.85-6.70 (m, 1H), 6.20 (d, J=16.6 Hz, 1H), 6.14-6.04 (m, 1H),5.77-5.67 (m, 1H), 4.58-3.88 (m, 3H), 3.25-3.10 (m, 1H), 2.99-2.84 (m,1H), 2.13 (s, 3H), 2.09-1.97 (m, 1H), 1.91-1.82 (m, 1H), 1.79-1.65 (m,1H), 1.64-1.50 (m, 1H).

Example 10:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-fluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 2-fluoro-4-phenoxyaniline in place of2-methyl-4-phenoxyaniline in step C and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₉H₂₄FN₅O₄S, 557.6; m/z found, 558.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.37 (s, 1H), 8.33 (d, J=5.4 Hz,1H), 8.22-8.05 (m, 1H), 7.64-7.51 (m, 1H), 7.51-7.38 (m, 2H), 7.28-7.20(m, 1H), 7.20-7.09 (m, 3H), 6.99-6.90 (m, 1H), 6.86-6.63 (m, 1H), 6.17(d, J=5.4 Hz, 1H), 6.07 (d, J=16.6 Hz, 1H), 5.65 (d, J=11.1 Hz, 1H),4.53-4.07 (m, 1H), 4.08-3.88 (m, 1H), 3.84-3.65 (m, 1H), 3.11-2.91 (m,1H), 2.78-2.56 (m, 1H), 2.00-1.83 (m, 1H), 1.80-1.69 (m, 1H), 1.68-1.54(m, 1H), 1.47-1.30 (m, 1H).

Example 11:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₉H₂₅N₅O₄S, 539.6; m/z found, 540.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.33-10.21 (m, 1H), 8.45-8.31 (m,2H), 7.50-7.42 (m, 2H), 7.42-7.36 (m, 1H), 7.25-7.18 (m, 1H), 7.16-7.07(m, 3H), 7.02-6.95 (m, 1H), 6.67-6.52 (m, 1H), 6.21-6.10 (m, 1H),6.04-5.96 (m, 1H), 5.72-5.64 (m, 1H), 4.57-4.42 (m, 1H), 3.92-3.59 (m,4H), 3.24-1.93 (m, 5H).

Example 12:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1 and using 2-chloro-4-fluoro-1-nitrobenzene in place of2-methyl-4-fluoro-1-nitrobenzene for step A, and using1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate 5) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₂ClN₅O₄S,560.0; m/z found, 560.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.40 (s,1H), 8.53-8.39 (m, 1H), 8.36-8.31 (m, 1H), 7.62 (d, J=8.6 Hz, 1H),7.51-7.45 (m, 2H), 7.35-7.31 (m, 1H), 7.26 (t, J=7.1 Hz, 1H), 7.22-7.16(m, 2H), 7.16-7.12 (m, 1H), 6.65-6.52 (m, 1H), 6.17-6.10 (m, 1H),6.08-6.02 (m, 1H), 5.70-5.63 (m, 1H), 4.57-4.40 (m, 1H), 3.90-3.70 (m,1H), 3.69-3.60 (m, 1H), 3.58-3.49 (m, 1H), 3.45-3.39 (m, 1H), 2.25-2.09(m, 1H), 2.02-1.92 (m, 1H).

Example 13:N-((3R,5S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3R,5S)-3-amino-5-hydroxypiperidine-1-carboxylate (Intermediate 2) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₅S,569.17; m/z found, 570.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ10.31-10.09 (m, 1H), 8.36 (d, J=5.3 Hz, 1H), 8.19-7.98 (m, 1H),7.53-7.35 (m, 3H), 7.27-7.16 (m, 1H), 7.18-7.06 (m, 3H), 7.04-6.94 (m,1H), 6.85-6.67 (m, 1H), 6.18-6.04 (m, 1H), 6.01 (d, J=5.3 Hz, 1H),5.77-5.62 (m, 1H), 4.33-4.13 (m, 1H), 4.06-3.79 (m, 2H), 3.10-2.87 (m,2H), 2.70-2.52 (m, 1H), 2.13-1.95 (m, 4H), 1.70-1.56 (m, 1H).

Example 14:N-((3R,5S)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1 and using tert-Butyl(3R,5S)-3-amino-5-methoxypiperidine-1-carboxylate (Intermediate 29) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₁H₂₉N₅O₅S,583.7; m/z found, 584.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.39-8.29 (m,1H), 7.47-7.36 (m, 2H), 7.30-7.27 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.03(m, 3H), 7.02-6.93 (m, 1H), 6.85-6.60 (m, 1H), 6.17-6.05 (m, 2H),5.79-5.60 (m, 1H), 4.44-4.26 (m, 1H), 4.23-4.12 (m, 1H), 4.03-3.92 (m,1H), 3.68-3.55 (m, 2H), 3.53-3.45 (m, 3H), 3.44-3.35 (m, 1H), 2.17-2.09(m, 4H), 2.02-1.96 (m, 1H).

Example 15:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1 and using 2-chloro-4-fluoro-1-nitrobenzene in place of5-fluoro-2-nitrotoluene in step A and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₉H₂₄ClN₅O₄S, 574.1; m/z found, 574.3[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d, J=5.6 Hz, 1H), 7.78-7.73 (m,1H), 7.52-7.45 (m, 1H), 7.36-7.21 (m, 2H), 7.10-7.02 (m, 2H), 7.00-6.88(m, 2H), 6.88-6.70 (m, 1H), 6.28-6.14 (m, 1H), 6.07 (d, J=5.6 Hz, 1H),5.81-5.66 (m, 1H), 4.63-3.87 (m, 3H), 3.25-3.10 (m, 1H), 3.01-2.82 (m,1H), 2.14 (s, 3H), 2.09-2.01 (m, 1H), 1.94-1.83 (m, 1H), 1.81-1.68 (m,1H), 1.65-1.52 (m, 1H).

Example 16:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(benzofuran-7-yloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using benzofuran-7-ol (Intermediate 8) in place ofphenol in step A, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₂H₂₇N₅O₅S, 593.7; m/z found, 594.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d, J=5.6 Hz, 1H), 7.78-7.73 (m,1H), 7.52-7.45 (m, 1H), 7.36-7.21 (m, 2H), 7.10-7.02 (m, 2H), 7.00-6.88(m, 2H), 6.88-6.70 (m, 1H), 6.28-6.14 (m, 1H), 6.07 (d, J=5.6 Hz, 1H),5.81-5.66 (m, 1H), 4.63-3.87 (m, 3H), 3.25-3.10 (m, 1H), 3.01-2.82 (m,1H), 2.14 (s, 3H), 2.09-2.01 (m, 1H), 1.94-1.83 (m, 1H), 1.81-1.68 (m,1H), 1.65-1.52 (m, 1H).

Example 17:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(2,6-difluorophenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using 2,6-difluorophenol in place of phenol instep A, and using (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₉H₂₃F₂N₅O₄S,575.6; m/z found, 576.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d,J=5.6 Hz, 1H), 7.38-7.27 (m, 2H), 7.22-7.11 (m, 2H), 7.04-6.99 (m, 1H),6.96-6.89 (m, 1H), 6.73-6.51 (m, 1H), 6.34-6.20 (m, 1H), 6.08-6.00 (m,1H), 5.80-5.64 (m, 1H), 4.71-4.54 (m, 1H), 4.02-3.49 (m, 4H), 2.41-2.01(m, 5H).

Example 18:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using 4-fluoronitrobenzene in place of5-fluoro-2-nitrotoluene in step A, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₉H₂₅N₅O₄S, 539.6; m/z found, 540.2[M+H]+. ¹H NMR (500 MHz, CD₃OD): δ 8.33 (d, J=5.6 Hz, 1H), 7.48-7.32 (m,4H), 7.27-7.07 (m, 5H), 6.90-6.68 (m, 1H), 6.21 (dd, J=14.0, 5.4 Hz,2H), 5.79-5.69 (m, 1H), 4.60-3.87 (m, 3H), 3.24-3.12 (m, 1H), 2.99-2.81(m, 1H), 2.15-1.46 (m, 4H).

Example 19:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(2-ethylphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using 2-ethylphenol in place of phenol in step A,and using (R)-tert-butyl 3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₂H₃₁N₅O₄S,581.7; m/z found, 582.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d,J=5.6 Hz, 1H), 7.36-7.30 (m, 1H), 7.27-7.20 (m, 2H), 7.18-7.12 (m, 1H),7.00-6.93 (m, 2H), 6.88-6.83 (m, 1H), 6.83-6.71 (m, 1H), 6.25-6.12 (m,1H), 6.05 (d, J=5.6 Hz, 1H), 5.78-5.66 (m, 1H), 4.62-4.11 (m, 2H),3.98-3.88 (m, 1H), 3.23-3.13 (m, 1H), 2.99-2.82 (m, 1H), 2.71-2.57 (m,2H), 2.12-2.05 (m, 4H), 1.91-1.81 (m, 1H), 1.76-1.55 (m, 2H), 1.23-1.13(m, 3H).

Example 20:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-fluoro-6-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 2-fluoro-6-methyl-4-phenoxyaniline(Intermediate 9) in place of 2-methyl-4-phenoxyaniline in step C, andusing (R)-tert-butyl 3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₀H₂₆FN₅O₄S,571.6; m/z found, 572.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.37 (d,J=5.5 Hz, 1H), 7.53-7.39 (m, 2H), 7.30-7.19 (m, 1H), 7.17-7.09 (m, 2H),6.93-6.68 (m, 3H), 6.26-6.11 (m, 2H), 5.84-5.63 (m, 1H), 4.62-3.83 (m,3H), 3.25-3.10 (m, 1H), 3.03-2.83 (m, 1H), 2.16 (s, 3H), 2.11-2.02 (m,1H), 1.95-1.52 (m, 3H).

Example 21:(R,E)-N-(1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 120 mg, 0.212 mmol), 3-methyloxetane-3-carbaldehyde (64mg, 0.64 mmol), piperidine (0.3 mL), acetic acid (0.1 mL), dioxane (10mL), and 4A molecular sieves (1 g) and the reaction mixture was stirredat 100° C. for 1 h under N2. The mixture was concentrated to dryness andpurified by flash column chromatography to yield the title compound (69mg, 50% yield) as a white solid. MS (ESI): mass calcd. for C₃₅H₃₂N₆O₅S,648.7; m/z found, 649.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33-8.27 (m,1H), 7.42-7.35 (m, 2H), 7.33-7.23 (m, 2H), 7.20-7.12 (m, 1H), 7.10-7.01(m, 3H), 6.99-6.92 (m, 1H), 6.07-6.01 (m, 1H), 5.08-4.92 (m, 1H),4.68-4.54 (m, 1H), 4.53-4.37 (m, 2H), 4.35-4.22 (m, 1H), 4.09-3.70 (m,3H), 3.65-3.36 (m, 1H), 2.15-2.01 (m, 4H), 1.99-1.73 (m, 2H), 1.69-1.57(m, 4H).

Example 22:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(benzofuran-7-yloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using benzofuran-7-ol (Intermediate 8) in place ofphenol in step A, and using (R)-tert-butyl3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₁H₂₅N₅O₅S, 579.6; m/z found, 580.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.36 (d, J=5.7 Hz, 1H), 7.77-7.73 (m,1H), 7.52-7.46 (m, 1H), 7.32-7.21 (m, 2H), 7.08-7.02 (m, 2H), 7.00-6.87(m, 2H), 6.70-6.53 (m, 1H), 6.33-6.24 (m, 1H), 6.12 (d, J=5.7 Hz, 1H),5.80-5.69 (m, 1H), 4.70-4.57 (m, 1H), 4.03-3.48 (m, 4H), 2.37-2.04 (m,5H).

Example 23:(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: tert-butyl(R,E)-methyl(4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate

The title compound was prepared in a manner analogous to Example 104(including Chiral resolution Method A after Step F to obtain the *Satropisomer), and using(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98) and (E)-4-[tert-Butoxycarbonyl(methyl)amino]but-2-enoicacid (Intermediate 10).

Step B:(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a flask containing tert-butyl(R,E)-methyl(4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate(52 mg, 0.075 mmol) was added MeOH (4.0 mL) and concentrated aqueous HCl(4.0 mL). The reaction mixture was stirred at rt for 1 h, then themixture was concentrated under reduced pressure and purified by silicagel chromatography to give the title compound (32 mg, 65%) as a whitesolid. MS (ESI): mass calcd. for C₃₂H₃₂N₆O₄S, 596.7; m/z found, 597.3[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.40 (s, 1H), 8.37-8.30 (m, 1H),7.44-7.37 (m, 2H), 7.34-7.27 (m, 1H), 7.21-7.14 (m, 1H), 7.13-7.04 (m,3H), 7.01-6.95 (m, 1H), 6.92-6.82 (m, 1H), 6.74-6.60 (m, 1H), 6.12-6.05(m, 1H), 4.54-3.91 (m, 3H), 3.84-3.75 (m, 2H), 3.25-3.08 (m, 1H),3.00-2.81 (m, 1H), 2.71 (s, 3H), 2.18-2.02 (m, 4H), 1.94-1.83 (m, 1H),1.82-1.67 (m, 1H), 1.66-1.53 (m, 1H).

Example 24:(R)-5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the method from Example 52 Step B,and using(R)-5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 78) in place of(R)-5-(4-(2,6-difluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.MS (ESI): mass calcd. for C₃₆H₃₂N₆O₄S, 644.7; m/z found, 645 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 8.30 (d, J=5.4 Hz, 1H), 8.07 (d, J=7.7 Hz,1H), 7.80-7.70 (m, 1H), 7.69-7.60 (m, 1H), 7.53-7.44 (m, 1H), 7.37-7.23(m, 3H), 7.17-7.05 (m, 3H), 7.04-6.93 (m, 1H), 5.95 (d, J=5.5 Hz, 1H),5.33 (s, 2H), 4.05-3.92 (m, 1H), 2.95-2.84 (m, 1H), 2.80-2.68 (m, 1H),2.27 (s, 3H), 2.05 (s, 3H), 2.03-1.93 (m, 2H), 1.85-1.65 (m, 2H),1.61-1.47 (m, 1H), 1.45-1.30 (m, 1H).

Example 25:(S,E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, and using (E)-4-hydroxybut-2-enoic acid (Intermediate 13) inplace of prop-2-enoyl chloride in step I. MS (ESI): mass calcd. forC₃₁H₂₉N₅O₅S, 583.7; m/z found, 584.6 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.33-8.29 (m, 1H), 7.42-7.35 (m, 2H), 7.33-7.28 (m, 1H), 7.19-7.12 (m,1H), 7.10-7.02 (m, 3H), 6.99-6.94 (m, 1H), 6.88-6.77 (m, 1H), 6.71-6.61(m, 1H), 6.08-6.03 (m, 1H), 4.53-3.90 (m, 5H), 3.24-3.12 (m, 1H),2.97-2.84 (m, 1H), 2.11 (s, 3H), 2.09-2.00 (m, 1H), 1.89-1.81 (m, 1H),1.77-1.65 (m, 1H), 1.63-1.50 (m, 1H).

Example 26:(R)—N-(1-(2-Chloroacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Example 104,using 2-chloroprop-2-enic acid and(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869). MS (ESI): mass calcd. for C₃₀H₂₆ClN₅O₄S, 588.1; m/zfound, 588.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.42-8.37 (m, 1H),7.44-7.35 (m, 2H), 7.33-7.28 (m, 1H), 7.20-7.13 (m, 1H), 7.11-7.03 (m,3H), 7.00-6.93 (m, 1H), 6.22-6.06 (m, 1H), 5.70 (s, 2H), 4.48-4.13 (m,1H), 4.12-3.83 (m, 2H), 3.25-3.12 (m, 1H), 2.99-2.82 (m, 1H), 2.12 (s,3H), 2.10-2.01 (m, 1H), 1.93-1.83 (m, 1H), 1.80-1.67 (m, 1H), 1.65-1.52(m, 1H).

Example 27:(R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: tert-butyl(R,E)-(4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate

The title compound was prepared in a manner analogous to Example 104,using tert-butyl (3R)-3-aminopiperidine-1-carboxylate and(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869).

Step B:(R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the conditions described in Step Bof Example 131 using tert-butyl(R,E)-(4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate.MS (ESI): mass calcd. for C₃₁H₃₀N₆O₄S, 582.7; m/z found, 583.4 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ 8.48 (s, 1H), 8.38-8.31 (m, 1H), 7.45-7.37(m, 2H), 7.33-7.27 (m, 1H), 7.22-7.14 (m, 1H), 7.14-7.03 (m, 3H),7.02-6.95 (m, 1H), 6.85-6.78 (m, 1H), 6.77-6.67 (m, 1H), 6.12-6.06 (m,1H), 4.57-3.89 (m, 3H), 3.78-3.71 (m, 2H), 3.25-3.08 (m, 1H), 2.97-2.80(m, 1H), 2.17-2.01 (m, 4H), 1.96-1.84 (m, 1H), 1.83-1.70 (m, 1H),1.67-1.53 (m, 1H).

Example 28:N-((3S,4R)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral resolution Method A after Step F to obtain the *Satropisomer) in Example 1, and using tert-butyl(3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₉H₂₄FN₅O₄S, 557.6; m/z found, 558.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.37-8.30 (m, 1H), 7.45-7.37 (m, 2H),7.33-7.26 (m, 1H), 7.21-7.14 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.92 (m,1H), 6.67-6.53 (m, 1H), 6.36-6.26 (m, 1H), 6.12-6.05 (m, 1H), 5.81-5.74(m, 1H), 5.39-5.16 (m, 1H), 4.19-3.84 (m, 3H), 3.81-3.52 (m, 2H), 2.12(s, 3H).

Example 29:(R,EZ)—N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 200 mg, 0.35 mmol), 2-ethoxy-2-methylpropanal (123 mg, 1.1mmol), piperdine (0.3 mL), and EtOH (5 mL) and was stirred at rt for 15h. Then the reaction mixture was concentrated to dryness and purified byflash column chromatography to yield the title compound (154 mg, 63.0%yield) as a light yellow solid. MS (ESI): mass calcd. for C₃₆H₃₆N₆O₅S,664.8; m/z found, 665.8 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35-8.31 (m,1H), 7.43-7.37 (m, 2H), 7.33-7.27 (m, 1H), 7.20-7.14 (m, 1H), 7.11-7.03(m, 3H), 7.00-6.95 (m, 1H), 6.92-6.69 (m, 1H), 6.12-6.05 (m, 1H),4.62-3.89 (m, 3H), 3.60-3.34 (m, 3H), 3.19-2.86 (m, 1H), 2.21-2.20 (m,4H), 1.96-1.85 (m, 1H), 1.80-1.62 (m, 2H), 1.50-1.21 (m, 9H).

Example 30:(R,E)-N-(1-(4-Hydroxybut-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the method in Example 104, andusing (E)-4-hydroxybut-2-enoic acid (Intermediate 13) in place ofmethylsulfonylpropanoic acid. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₅S,569.6; m/z found, 570.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.24 (s,1H), 8.32 (d, J=5.4 Hz, 1H), 7.49-7.40 (m, 2H), 7.36 (d, J=8.6 Hz, 1H),7.23-7.15 (m, 1H), 7.14-7.03 (m, 3H), 7.02-6.90 (m, 1H), 6.81-6.67 (m,1H), 6.46-6.25 (m, 1H), 5.96 (d, J=5.2 Hz, 1H), 5.09-4.90 (m, 1H),4.57-4.37 (m, 1H), 4.21-4.05 (m, 2H), 3.88-3.38 (m, 4H), 2.22-2.08 (m,1H), 2.05 (s, 3H), 2.01-1.90 (m, 1H).

Example 31: N-(4-Cyano-1,4-oxazepan-6-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl6-amino-1,4-oxazepane-4-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, and using bromocyanide in place of prop-2-enoyl chloride in stepI. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₄S, 540.6; m/z found, 541.5[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 8.40-8.26 (m, 1H),8.19 (s, 1H), 7.49-7.37 (m, 2H), 7.37-7.28 (m, 1H), 7.21-7.14 (m, 1H),7.14-7.02 (m, 3H), 6.99-6.91 (m, 1H), 6.04-5.86 (m, 1H), 4.38-4.22 (m,1H), 3.90-3.81 (m, 1H), 3.80-3.66 (m, 3H), 3.57-3.50 (m, 1H), 3.41-3.35(m, 3H), 2.03 (s, 3H).

Example 32:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(cyclohexloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:2-Chloro-4-[4-(cyclohexoxy)-2-methylanilino]pyridine-3-carbonitrile

To a round bottom flask containing2-chloro-4-(4-hydroxy-2-methylanilino)pyridine-3-carbonitrile(Intermediate 14) (1 g, 4 mmol), cyclohexanol (1.16 g, 11.6 mmol), PPh₃(1.5 g, 5.7 mmol), and THF (20 mL) at 0° C. was added DIAD (1.17 g, 5.79mmol). The mixture was stirred at rt overnight. The mixture wasconcentrated to dryness and the residue was purified by flash columnchromatography to yield the title compound (400 mg, 30% yield) as ayellow solid.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(cyclohexyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsD-I in Example 1, and using2-chloro-4-[4-(cyclohexoxy)-2-methylanilino]pyridine-3-carbonitrile inplace of 2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrilein step D, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₀H₃₃N₅O₄S,559.7; m/z found, 560.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.43 (s, 1H),8.30 (d, J=5.5 Hz, 1H), 7.23-7.15 (m, 1H), 7.02-6.95 (m, 1H), 6.94-6.89(m, 1H), 6.87-6.71 (m, 1H), 6.27-6.14 (m, 1H), 6.03 (d, J=5.5 Hz, 1H),5.79-5.67 (m, 1H), 4.55-3.88 (m, 4H), 3.25-3.11 (m, 1H), 3.01-2.80 (m,1H), 2.10 (s, 3H), 2.06-1.94 (m, 3H), 1.90-1.69 (m, 4H), 1.65-1.36 (m,7H).

Example 33:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 4-Isopropoxy-2-methyl-1-nitrobenzene

To a round bottom flask were added 3-methyl-4-nitrophenol (5.0 g, 33mmol), K₂CO₃ (9.0 g, 65 mmol), DMF (20 mL), and 2-iodopropane (8.3 g,460 mmol) and the reaction was stirred at 80° C. overnight. Water wasadded to the mixture and a yellow precipitate formed. The mixture wasfiltered and the precipitate was washed with water and dried undervacuum to yield the title compound (5.0 g, 78% yield).

Step B: 4-Isopropoxy-2-methylaniline

To a round bottom flask were added 4-isopropoxy-2-methyl-1-nitrobenzene(5.0 g, 26 mmol) and MeOH (100 mL). The reaction mixture was evacuatedunder reduced pressure and filled with N₂ (3×) and Pd/C (10% on carbon;500 mg) was added. The mixture was evacuated under reduced pressure andfilled with N₂ (3×), then evacuated under reduced pressure and filledwith H₂. The mixture was stirred under H₂ atmosphere overnight. Themixture was filtered over diatomaceous earth and concentrated to drynessto yield the title compound (3.5 g, 83% yield).

Step C: 2-Chloro-4-(4-isopropoxy-2-methylanilino)pyridine-3-carbonitrile

To a round bottom flask were added 4-isopropoxy-2-methylaniline (1 g, 6mmol), 2-chloro-4-iodopyridine-3-carbonitrile (2.0 g, 7.6 mmol),DPEPhos[bis(2-diphenylphosphinophenyl)ether] (650 mg, 1.2 mmol),palladium(II) acetate (135 mg, 0.600 mmol), and K₃PO₄ (3.5 g, 16 mmol).The reaction mixture was degassed and heated at 120° C. overnight. Themixture was cooled to rt, concentrated to dryness, and purified by flashcolumn chromatography to yield the title compound (2.34 g, 65.0% yield)as a yellow solid.

Step D:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsD-I in Example 1, and using2-chloro-4-(4-isopropoxy-2-methylanilino)pyridine-3-carbonitrile inplace of 2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrilein step D, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₉N₅O₄S,519.6; m/z found, 520.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.18 (s,1H), 8.30 (d, J=5.4 Hz, 1H), 8.18-8.01 (m, 1H), 7.33-7.15 (m, 1H),7.04-6.87 (m, 2H), 6.85-6.67 (m, 1H), 6.22-6.02 (m, 1H), 5.89 (d, J=5.4Hz, 1H), 5.74-5.60 (m, 1H), 4.78-4.56 (m, 1H), 4.57-3.86 (m, 2H),3.84-3.68 (m, 1H), 3.17-2.90 (m, 1H), 2.85-2.59 (m, 1H), 2.03 (s, 3H),1.98-1.88 (m, 1H), 1.82-1.55 (m, 2H), 1.52-1.36 (m, 1H), 1.35-1.24 (m,6H).

Example 34:N-((3S,4R)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3S,4R)-3-amino-4-methoxypyrrolidine-1-carboxylate (Intermediate 11) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₅S,569.6; m/z found, 570.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ8.29 (d, J=5.4 Hz, 1H), 7.44-7.35 (m, 2H), 7.32-7.26 (m, 1H), 7.18-7.10(m, 1H), 7.10-7.00 (m, 3H), 6.98-6.90 (m, 1H), 6.62-6.47 (m, 1H),6.23-6.10 (m, 1H), 5.98 (d, J=5.5 Hz, 1H), 5.72-5.63 (m, 1H), 4.75-4.49(m, 1H), 4.05-3.90 (m, 2H), 3.82-3.60 (m, 2H), 3.52-3.41 (m, 1H),3.36-3.27 (m, 3H), 2.05 (s, 3H).

Example 35:(R)—N-(1-Cyanopiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral resolution Method A after Step F to obtain the *Satropisomer) in Example 1, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, and using bromocyanide in place of prop-2-enoyl chloride in stepI. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₃S, 524.6; m/z found, 525.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.18 (br, 1H), 8.36-8.25 (m, 1H),8.23-8.08 (br, 1H), 7.46-7.39 (m, 2H), 7.37-7.30 (m, 1H), 7.20-7.16 (m,1H), 7.13-7.05 (m, 3H), 6.99-6.92 (m, 1H), 6.00-5.86 (m, 1H), 3.97-3.90(m, 1H), 2.98-2.90 (m, 2H), 2.03 (s, 3H), 2.01-1.90 (m, 1H), 1.90-1.83(m, 1H), 1.82-1.73 (m, 1H), 1.66-1.51 (m, 2H), 1.51-1.34 (m, 1H).

Example 36: N-((3S,4S)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3S,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₉H₂₄FN₅O₄S, 557.6; m/z found, 558.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d, J=5.5 Hz, 1H), 7.47-7.37 (m,2H), 7.34-7.27 (m, 1H), 7.24-7.13 (m, 1H), 7.13-7.02 (m, 3H), 7.02-6.94(m, 1H), 6.70-6.56 (m, 1H), 6.39-6.28 (m, 1H), 6.08 (d, J=5.5 Hz, 1H),5.83-5.74 (m, 1H), 5.35-5.16 (m, 1H), 4.76-4.65 (m, 1H), 4.10-3.74 (m,4H), 2.12 (s, 3H).

Example 37:N-((3S,4R)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₉H₂₄FN₅O₄S, 557.6; m/z found, 558.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ 8.28 (d, J=5.2 Hz, 1H),7.42-7.21 (m, 3H), 7.16-7.07 (m, 1H), 7.07-6.97 (m, 3H), 6.95-6.88 (m,1H), 6.61-6.45 (m, 1H), 6.25-6.15 (m, 1H), 5.98 (d, J=5.4 Hz, 1H),5.74-5.64 (m, 1H), 5.35-5.10 (m, 1H), 4.81-4.61 (m, 1H), 4.06-3.84 (m,2H), 3.80-3.47 (m, 2H), 2.04 (s, 3H).

Example 38:(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Example 104,using (E)-4-[tert-Butoxycarbonyl(methyl)amino]but-2-enoic acid(Intermediate 10) and(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98). MS (ESI): mass calcd. for C₃₂H₃₂N₆O₄S, 596.7; m/z found,597.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.46 (s, 1H), 8.38-8.31 (m,1H), 7.45-7.37 (m, 2H), 7.33-7.27 (m, 1H), 7.22-7.14 (m, 1H), 7.14-7.03(m, 3H), 7.02-6.95 (m, 1H), 6.92-6.83 (m, 1H), 6.74-6.61 (m, 1H),6.12-6.06 (m, 1H), 4.57-3.89 (m, 3H), 3.86-3.76 (m, 2H), 3.25-3.08 (m,1H), 2.97-2.83 (m, 1H), 2.71 (s, 3H), 2.17-2.01 (m, 4H), 1.96-1.84 (m,1H), 1.83-1.70 (m, 1H), 1.67-1.53 (m, 1H).

Example 39:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(cyclohexyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared as for using steps A-I in Example 33,and using iodocyclohexane in place of 2-iodopropane in Step 1 andtert-butyl (3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(R)-3-aminopiperidine-1-carboxylate in Step G. MS (ESI): mass calcd. forC₂₉H₃₁N₅O₄S, 545.7; m/z found, 546.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.33 (d, J=5.6 Hz, 1H), 7.30-7.20 (m, 1H), 7.04-6.99 (m, 1H), 6.98-6.93(m, 1H), 6.73-6.55 (m, 1H), 6.37-6.26 (m, 1H), 6.06 (d, J=5.6 Hz, 1H),5.85-5.71 (m, 1H), 4.73-4.58 (m, 1H), 4.47-4.36 (m, 1H), 4.07-3.52 (m,4H), 2.43-2.11 (m, 5H), 2.07-2.00 (m, 2H), 1.89-1.80 (m, 2H), 1.68-1.41(m, 6H).

Example 40:(R,E)-N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 250 mg, 0.44 mmol), 2-methoxy-2-methylpropanal (225 mg,2.2 mmol), EtOH (5 mL), and piperdine (75 mL) The reaction mixture wasstirred at rt for 1 h, concentrated to dryness, and purified by flashcolumn chromatography to yield the title compound (80 mg, 28% yield) asa white solid. MS (ESI): mass calcd. for C₃₅H₃₄N₆O₅S, 650.7; m/z found,651.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d, J=5.6 Hz, 1H),7.47-7.36 (m, 2H), 7.34-7.26 (m, 1H), 7.22-7.14 (m, 1H), 7.12-7.02 (m,3H), 7.01-6.94 (m, 1H), 6.92-6.69 (m, 1H), 6.06 (d, J=5.5 Hz, 1H),4.56-3.83 (m, 3H), 3.6-3.32 (m, 1H), 3.29-3.22 (m, 3H), 3.18-2.82 (m,1H), 2.17-2.02 (m, 4H), 1.98-1.84 (m, 1H), 1.81-1.57 (m, 2H), 1.51-1.32(m, 6H).

Example 41:(R,E)-N-(1-(2-Cyano-3-¹³C-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: ¹³C-Cyclopropanecarbaldehyde

A solution of ¹³C-DMF (500 mg, 6.75 mmol) in THF (10 mL) was slowlyadded to cyclopropane magnesium bromide in THF (0.5 M, 14.8 mL, 7.42mmol) cooled in an ice bath under N₂ over a period of 5 minutes. Themixture was brought to room temperature and stirred for 1 h. The mixturewas acidified with 3 M aqueous HCl, extracted with Et₂O, dried overanhydrous Na₂SO₄, and concentrated to dryness to give the title compoundas a pale yellow oil, which was used in the next step withoutpurification.

Step B:(R,E)-N-(1-(2-Cyano-3-¹³C-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 200 mg, 0.35 mmol) and ¹³C-cyclopropanecarbaldehyde (100mg, 1.4 mmol) in EtOH (5 mL) was added piperidine (60 mg, 0.70 mmol) andwas stirred at room temperature overnight. The reaction was concentratedto dryness and purified by normal phase flash column chromatography(SiO₂) to give the title compound (22 mg, 91% yield) as a yellow solid.MS (ESI): mass calcd. for C₃₄H₃₀N₆O₄S, 619.7; m/z found, 620.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ 8.28 (d, J=5.6 Hz, 1H), 7.39-7.31 (m, 2H),7.28-7.21 (m, 1H), 7.16-7.07 (m, 1H), 7.07-6.96 (m, 3H), 6.95-6.85 (m,1H), 6.72-6.19 (m, 1H), 5.98 (d, J=5.6 Hz, 1H), 4.24-4.08 (m, 3H),3.99-3.83 (m, 2H), 2.04 (s, 3H), 1.98-1.88 (m, 2H), 1.83-1.74 (m, 1H),1.69-1.60 (m, 1H), 1.54-1.45 (m, 1H), 1.16-1.05 (m, 2H), 0.95-0.83 (m,1H), 0.81-0.74 (m, 1H).

Example 42:(R)—N-(1-(But-2-ynoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the method in Example 104, andusing but-2-ynoic acid in place of 3-methylsulfonylpropanoic acid. MS(ESI): mass calcd. for C₃₁H₂₇N₅O₄S, 565.6; m/z found, 566.2 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD and DMSO-d₆): δ 8.32-8.27 (m, 1H), 7.40-7.33 (m,2H), 7.31-7.26 (m, 1H), 7.17-7.10 (m, 1H), 7.09-7.00 (m, 3H), 6.96-6.89(m, 1H), 6.00-5.95 (m, 1H), 4.40-3.73 (m, 3H), 3.29-3.02 (m, 1H),2.92-2.64 (m, 1H), 2.07 (s, 3H), 1.99-1.91 (m, 4H), 1.85-1.73 (m, 1H),1.69-1.59 (m, 1H), 1.53-1.37 (m, 1H).

Example 43:(R,E)-N-(1-(2-Cyano-4-methyl-4-morpholinopent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Example 104,using 2-cyanoacetic acid and(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98).

Step B:(R,E)-N-(1-(2-Cyano-4-methyl-4-morpholinopent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a sealed tube were added(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(50 mg, 0.09 mmol), 2-methyl-2-morpholinopropanal (20 mg, 0.13 mmol),piperidine (9 mg, 0.1 mmol), and EtOH (3 mL). The sealed tube was heatedto 105° C. overnight, cooled to rt, and the residue purified by flashcolumn chromatography to yield the title compound (39 mg, 63% yield) asa yellow solid. MS (ESI): mass calcd. for C₃₈H₃₉N₇O₅S, 705.8; m/z found,706.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d, J=5.5 Hz, 1H),7.47-7.37 (m, 2H), 7.33-7.26 (m, 1H), 7.23-7.14 (m, 1H), 7.12-7.03 (m,3H), 7.01-6.94 (m, 1H), 6.90-6.78 (m, 1H), 6.07 (d, J=5.6 Hz, 1H),4.55-3.82 (m, 3H), 3.81-3.63 (m, 4H), 3.47-3.35 (m, 0.5H), 3.29-2.86 (m,1.5H), 2.71-2.51 (m, 4H), 2.12 (s, 3H), 2.07-1.60 (m, 4H), 1.41-1.24 (m,6H).

Example 44:(S)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1 (including Chiral resolution Method A after Step F toobtain the *S atropisomer), and using tert-butyl(3S)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₄S, 553.6; m/z found, 554.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.29 (d, J=6.5 Hz, 1H), 7.47-7.33 (m,2H), 7.29 (d, J=8.4 Hz, 1H), 7.24-6.94 (m, 5H), 6.88-6.73 (m, 1H), 6.20(d, J=17.3 Hz, 1H), 6.13-5.97 (m, 1H), 5.80-5.62 (m, 1H), 4.64-3.88 (m,3H), 3.26-3.12 (m, 1H), 3.04-2.89 (m, 1H), 2.18-2.02 (m, 4H), 1.99-1.47(m, 3H).

Example 45:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-fluoro-6-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-G in Example 1, and using 2-fluoro-6-methyl-4-phenoxyaniline(Intermediate 9) in place of 2-methyl-4-phenoxyaniline in step C, andusing 1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate 5) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₉H₂₄FN₅O₄S,557.6; m/z found, 558.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.36-8.28(br, 1H), 7.57-7.41 (m, 2H), 7.34-7.10 (m, 3H), 6.95-6.85 (m, 1H),6.83-6.76 (m, 1H), 6.75-6.55 (m, 1H), 6.42-6.25 (m, 1H), 6.17-6.04 (m,1H), 5.86-5.70 (m, 1H), 4.77-4.57 (m, 1H), 4.18-3.51 (m, 4H), 2.48-1.94(m, 5H).

Example 46:(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(1-propioloylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using a method analogous to Example 75,using prop-2-ynoic acid and(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98). MS (ESI): mass calcd. for C₃₀H₂₅N₅O₄S, 551.6; m/z found,552.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.40-8.26 (m, 1H), 7.43-7.34(m, 2H), 7.29-7.21 (m, 1H), 7.20-7.13 (m, 1H), 7.12-7.03 (m, 3H),7.00-6.93 (m, 1H), 6.09-6.03 (m, 1H), 4.50-4.36 (m, 1H), 4.33-4.13 (m,1H), 4.05-3.77 (m, 2H), 3.38-3.19 (m, 1H), 3.06-2.85 (m, 1H), 2.16-2.01(m, 4H), 1.95-1.84 (m, 1H), 1.79-1.67 (m, 1H), 1.64-1.49 (m, 1H).

Example 47:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using a method analogous to Example 75,using (E)-2-cyano-3-cyclopropylprop-2-enoic acid (Intermediate 17) and(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860). MS (ESI): mass calcd. for C₃₃H₂₈N₆O₄S, 604.7; m/z found,605.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.32 (dd, J=5.7, 1.6 Hz, 1H),7.50-7.31 (m, 4H), 7.29-6.99 (m, 5H), 6.63-6.46 (m, 1H), 6.28-6.10 (m,1H), 5.48 (d, J=1.4 Hz, 1H), 4.53-3.87 (m, 3H), 2.21-0.70 (m, 11H).

Example 48:(R)—N-(1-(2-Fluoroacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using a method analogous to Example 75,using 2-fluoroprop-2-enoic acid and(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869). MS (ESI): mass calcd. for C₃₀H₂₆FN₅O₄S, 571.6; m/z found,572.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.32 (d, J=5.6 Hz, 1H),7.46-7.35 (m, 2H), 7.32-7.23 (m, 1H), 7.21-7.12 (m, 1H), 7.12-7.02 (m,3H), 7.00-6.91 (m, 1H), 6.09-6.05 (m, 1H), 5.28-5.06 (m, 2H), 4.51-3.84(m, 3H), 3.25-2.85 (m, 2H), 2.11 (s, 3H), 2.09-1.99 (m, 1H), 1.96-1.82(m, 1H), 1.77-1.53 (m, 2H).

Example 49:(R)—N-(1-(2-Fluoroacryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98, 31 mg, 0.062 mmol), were added DMF (3 mL), 2-fluoroacrylicacid (9 mg, 0.01 mmol), triethylamine (21 mg, 0.188 mmol), HATU (47 mg,0.124 mmol). The reaction mixture was stirred at rt for 2 h. Water wasadded and the precipitate was collected by filtration, then purified bysilica gel chromatograph to give the title compound as a light yellowsolid. MS (ESI): mass calcd. for C₃₀H₂₆FN₅O₄S, 571.6; m/z found, 572.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34 (d, J=5.5 Hz, 1H), 7.47-7.36 (m,2H), 7.33-7.25 (m, 1H), 7.22-7.14 (m, 1H), 7.13-7.03 (m, 3H), 7.02-6.94(m, 1H), 6.08 (d, J=5.6 Hz, 1H), 5.30-5.10 (m, 2H), 4.63-3.77 (m, 3H),3.29-2.75 (m, 2H), 2.15 (s, 3H), 2.10-2.00 (m, 1H), 1.95-1.84 (m, 1H),1.80-1.69 (m, 1H), 1.67-1.55 (m, 1H).

Example 50:N-((3S,4S)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₉H₂₅N₅O₅S,555.6; m/z found, 556.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.31 (d,J=5.5 Hz, 1H), 7.45-7.35 (m, 2H), 7.35-7.27 (m, 1H), 7.21-7.12 (m, 1H),7.11-7.00 (m, 3H), 7.00-6.93 (m, 1H), 6.66-6.54 (m, 1H), 6.34-6.24 (m,1H), 6.06 (d, J=5.5 Hz, 1H), 5.76 (dt, J=10.5, 1.9, 1H), 4.50-4.32 (m,2H), 4.09-3.49 (m, 4H), 2.11 (s, 3H).

Example 51:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-cyclopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 4-(Cyclopropoxy)-2-methyl-1-nitrobenzene

To a reaction vial were added 3-methyl-4-nitrophenol (3.1 g, 20 mmol),bromocyclopropane (4.9 g, 40 mmol), KI (3.4 g, 20 mmol), cesiumcarbonate (6.6 g, 20 mmol), and NMP (20 mL) and was heated to 170° C.for 2 h in the microwave. The mixture was diluted with EtOAc, washedwith brine, dried over anhydrous Na₂SO₄, concentrated to dryness, andpurified by flash column chromatography to yield the title compound(0.85 g, 22% yield) as a brown liquid.

Step B: 4-(Cyclopropoxy)-2-methylaniline

A mixture of 4-(cyclopropoxy)-2-methyl-1-nitrobenzene (450 mg, 2.3 mmol)and Pd/C (24 mg, 0.23 mmol) in MeOH (15 mL) was stirred for 5 h underH₂. The reaction was filtered and the filtrate was concentrated todryness to yield the title compound (310 mg, 82% yield) as a brownliquid, which was used in the next step without purification.

Step C:2-Chloro-4-[4-(cyclopropoxy)-2-methylanilino]pyridine-3-carbonitrile

To a round bottom flask were added 4-(cyclopropoxy)-2-methylaniline (420mg, 2.6 mmol), 2-chloro-4-iodopyridine-3-carbonitrile (885 mg, 3.35mmol), Pd(OAc)₂ (58 mg, 0.26 mmol), DPEphos (280 mg, 0.51 mmol), cesiumcarbonate (1.7 g, 5.2 mmol), and dioxane (20 mL) and was stirred at 110°C. for 15 h under N2. The mixture was concentrated to dryness andpurified by flash column chromatography to yield the title compound (530mg, 69% yield) as a light yellow solid.

Step D:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-cyclopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsD-I in Example 1, and using2-chloro-4-[4-(cyclopropoxy)-2-methylanilino]pyridine-3-carbonitrile inplace 2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrile instep D, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) in step G. MS (ESI): mass calcd. for C₂₇H₂₇N₅O₄S,517.6; m/z found, 518.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35-8.26 (m,1H), 7.27-7.20 (m, 1H), 7.15-7.04 (m, 2H), 6.85-6.71 (m, 1H), 6.24-6.13(m, 1H), 6.07-6.00 (m, 1H), 5.77-5.67 (m, 1H), 4.61-3.87 (m, 3H),3.87-3.76 (m, 1H), 3.22-3.08 (m, 1H), 2.96-2.81 (m, 1H), 2.16-1.98 (m,4H), 1.92-1.80 (m, 1H), 1.79-1.65 (m, 1H), 1.64-1.50 (m, 1H), 0.88-0.77(m, 2H), 0.76-0.67 (m, 2H).

Example 52:(R)-5-(4-(2,6-Difluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(2,6-Difluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, using 2,6-difluorophenol in place of phenol in step A,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) in step G.

Step B:(R)-5-(4-(2,6-Difluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added(R)-5-(4-(2,6-difluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(120 mg, 0.22 mmol) and DCM (5 mL) and was treated with formaldehyde(0.5 mL, 37 wt. % in H₂O). To the stirred reaction was added NaBH(AcO)₃(95 mg, 0.45 mmol) and the reaction was maintained at rt for 1 h. Thereaction was concentrated to dryness and the residue purified by flashcolumn chromatography to yield the title compound (59 mg, 43% yield) asa yellow solid. MS (ESI): mass calcd. for C₂₈H₂₅F₂N₅O₃S, 549.6; m/zfound, 550.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 8.33-8.25 (m, 1H),8.12-8.00 (m, 1H), 7.48-7.29 (m, 4H), 7.11-7.05 (m, 1H), 6.99-6.89 (m,1H), 5.94-5.84 (m, 1H), 4.01-3.93 (m, 1H), 2.90-2.84 (m, 1H), 2.76-2.69(m, 1H), 2.25 (s, 3H), 2.07 (s, 3H), 2.01-1.96 (m, 2H), 1.91 (s, 3H),1.84-1.76 (m, 1H), 1.76-1.67 (m, 1H), 1.62-1.49 (m, 1H), 1.44-1.32 (m,1H).

Example 53:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:2-Chloro-4-[(5-chloro-1,3-benzodioxol-4-yl)amino]pyridine-3-carbonitrile

A mixture of 2,4-dichloropyridine-3-carbonitrile (1.6 g, 9.3 mmol),5-chloro-1,3-benzodioxol-4-amine (1.6 g, 9.3 mmol), DPEphos (1.0 g, 1.9mmol), Pd(AcO)₂ (0.21 g, 0.93 mmol), and K₃PO₄ (5.0 g, 23 mmol) indioxane (80 mL) was heated at reflux under N₂ overnight. The reactionwas concentrated to dryness and the residue was purified by flash columnchromatography to yield the title compound (2.2 g, 77% yield) as ayellow solid.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsD-I in Example 1 (including Chiral resolution Method A after Step F toobtain the *S atropisomer), and using2-chloro-4-[(5-chloro-1,3-benzodioxol-4-yl)amino]pyridine-3-carbonitrilein place of2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrile in step D,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) in step G. MS (ESI): mass calcd. forC₂₄H₂₀ClN₅O₅S, 526.0; m/z found, 526.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):δ 8.38 (d, J=5.5 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.4 Hz,1H), 6.85-6.70 (m, 1H), 6.25 (d, J=5.5 Hz, 1H), 6.23-6.15 (m, 1H),6.11-6.07 (m, 2H), 5.78-5.65 (m, 1H), 4.56-4.48 (m, 0.5H), 4.31-4.23 (m,0.5H), 4.20-4.12 (m, 0.5H), 4.05-3.87 (m, 1.5H), 3.25-3.11 (m, 1H),2.97-2.85 (m, 1H), 2.12-2.01 (m, 1H), 1.91-1.82 (m, 1H), 1.79-1.65 (m,1H), 1.63-1.52 (m, 1H).

Example 54:N-((3S,4S)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3S,4S)-3-amino-4-methoxypyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₅S,569.6; m/z found, 570.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d,J=5.3 Hz, 1H), 7.46-7.36 (m, 2H), 7.35-7.26 (m, 1H), 7.22-7.13 (m, 1H),7.13-7.02 (m, 3H), 7.02-6.94 (m, 1H), 6.68-6.53 (m, 1H), 6.37-6.23 (m,1H), 6.08 (d, J=5.5 Hz, 1H), 5.83-5.71 (m, 1H), 4.66-4.56 (m, 1H),4.08-3.77 (m, 3H), 3.75-3.62 (m, 2H), 3.52-3.45 (m, 3H), 2.12 (s, 3H).

Example 55:(R)—N-(1-(But-2-ynoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1 (including Chiral resolution Method A after Step F toobtain the *S atropisomer), and using tert-butyl(3S,4S)-3-amino-4-methoxypyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)—N-(1-(But-2-vnoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A mixture of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98, 25 mg, 0.050 mmol), but-2-ynoic acid (25 mg, 0.30 mmol),HATU (50 mg, 0.13 mmol), and triethylamine (20 mg, 0.20 mmol) in DMF (2mL) was reacted at rt for 2 h. The reaction was quenched with H₂O (20mL), extracted with DCM, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by flash columnchromatography to yield the title compound as a white solid. MS (ESI):mass calcd. for C₃₁H₂₇N₅O₄S, 565.6; m/z found, 566.4 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.38-8.27 (m, 1H), 7.46-7.36 (m, 2H), 7.33-7.26 (m, 1H),7.22-7.14 (m, 1H), 7.12-7.04 (m, 3H), 7.00-6.92 (m, 1H), 6.11-6.04 (m,1H), 4.48-4.22 (m, 2H), 4.13-3.92 (m, 1H), 3.40-3.16 (m, 1H), 3.06-2.80(m, 1H), 2.12 (s, 3H), 2.08-1.97 (m, 4H), 1.94-1.80 (m, 1H), 1.79-1.67(m, 1H), 1.66-1.51 (m, 1H).

Example 56:(R)—N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: tert-ButylN-[(3R)-1-[2-(dimethylamino)acetyl]-3-piperidyl]carbamate

A solution of tert-butyl N-[(3R)-3-piperidyl]carbamate (400 mg, 2 mmol),2-(dimethylamino)acetic acid (226 mg, 2.19 mmol), HATU (0.91 mg, 2.4mmol), and triethylamine (0.56 mL, 4.0 mmol) in DMF (5 mL) was stirredat rt overnight, then poured into water. The mixture was extracted withEtOAc and the combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness to yield thetitle compound as a yellow oil.

Step B:(R)—N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1 (including Chiral resolution Method A after Step F toobtain the *S atropisomer), and using1-[(3R)-3-amino-1-piperidyl]-2-(dimethylamino)ethanone (Intermediate 43)in place of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₁H₃₂N₆O₄S,584.7; m/z found, 585.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.26 (d,J=5.5 Hz, 1H), 7.43-7.34 (m, 2H), 7.29-7.21 (m, 1H), 7.20-7.13 (m, 1H),7.12-7.03 (m, 3H), 7.00-6.93 (m, 1H), 6.00 (d, J=5.5 Hz, 1H), 4.26-3.74(m, 3H), 3.61-3.40 (m, 2H), 3.27-3.04 (m, 2H), 2.49-2.34 (m, 6H), 2.12(s, 3H), 2.05-1.96 (m, 1H), 1.93-1.70 (m, 2H), 1.68-1.52 (m, 1H).

Example 57:(R)-5-(4-(2-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(2-Fluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of5-(4-(2-fluorophenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (218 mg, 0.501 mmol), tert-butyl(3R)-3-aminopiperidine-1-carboxylate (100 mg, 0.5 mmol), and HATU (380mg, 1.0 mmol) in DMF (3 mL) was stirred at rt for 3 hr. Water was addedand the precipitate that formed was filtered to give a pale yellowsolid. The solid was dissolved in MeOH (4 mL) and HCl (4 mL), and theresulting mixture was heated to 50° C. for 30 min. The reaction wasconcentrated to dryness to yield the title compound (200 mg, 72% yield)as a yellow solid, which was used in the next step reaction withoutfurther purification.

Step B:(R)-5-(4-(2-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(2-fluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(110 mg, 0.21 mmol) and formaldehyde (0.3 mL, 37 wt. % in H₂O) in MeOH(5 mL) was added NaBH(OAc)₃ (135 mg, 0.640 mmol) and was stirred at rtfor 1 h. The reaction was concentrated to dryness and purified by flashcolumn chromatography to yield the title compound (67 mg, 54% yield) asa white solid. MS (ESI): mass calcd. for C₂₈H₂₆FN₅O₃S, 531.6; m/z found,532.4 [M+H]+. ¹H NMR (400 MHz, CD₃OD): δ 8.54 (s, 1H), 8.33-8.21 (m,1H), 7.39-7.31 (m, 1H), 7.31-7.18 (m, 4H), 7.06-6.98 (m, 1H), 6.98-6.88(m, 1H), 6.06-5.97 (m, 1H), 4.32-4.19 (m, 1H), 3.44-3.33 (m, 1H),3.22-3.08 (m, 1H), 2.77-2.60 (m, 5H), 2.15-2.06 (m, 3H), 2.04-1.90 (m,2H), 1.88-1.74 (m, 1H), 1.69-1.55 (m, 1H).

Example 58:N-((3S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3S,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate (Intermediate 24) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₉H₂₅N₅O₅S,555.6; m/z found, 556.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30 (d,J=5.5 Hz, 1H), 7.44-7.35 (m, 2H), 7.33-7.27 (m, 1H), 7.19-7.12 (m, 1H),7.12-7.01 (m, 3H), 7.00-6.93 (m, 1H), 6.67-6.51 (m, 1H), 6.32-6.22 (m,1H), 6.05 (d, J=5.5 Hz, 1H), 5.80-5.68 (m, 1H), 4.65-4.52 (m, 1H),4.51-4.38 (m, 1H), 4.06-3.85 (m, 1H), 3.73-3.49 (m, 3H), 2.10 (s, 3H).

Example 59:(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a mixture of(R)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 18) (50 mg, 0.1 mmol) and formaldehyde (0.3 mL, 37 wt. %in H₂O) in MeOH (6 mL) was added NaBH(OAc)₃ (62 mg, 0.29 mmol). Thereaction mixture was stirred at rt for 1 h, concentrated to dryness, andpurified by flash column chromatography to yield the title compound (36mg, 64% yield) as a white solid. MS (ESI): mass calcd. for C₂₈H₂₆FN₅O₃S,531.6; m/z found, 532.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.48 (s, 1H),8.39-8.29 (m, 1H), 7.43-7.34 (m, 2H), 7.23-7.11 (m, 2H), 7.11-7.03 (m,3H), 6.18-6.10 (m, 1H), 4.31-4.21 (m, 1H), 3.50-3.36 (m, 1H), 3.26-3.16(m, 1H), 2.82-2.64 (m, 5H), 2.12 (s, 3H), 2.04-1.96 (m, 2H), 1.88-1.77(m, 1H), 1.70-1.57 (m, 1H).

Example 60:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.30 mmol) in MeOH (5 mL) was added propanal(0.045 mL, 0.6 mmol). It was stirred at rt for 10 min, then NaBH(OAc)₃(190 mg, 0.90 mmol) was added and the mixture was stirred at rtovernight. The pH was adjusted to pH>7 with 2 M aqueous NaOH andconcentrated to dryness. The residue was purified by flash columnchromatography to yield the title compound (75 mg, 46% yield) as ayellow solid. MS (ESI): mass calcd. for C₃₀H₃₁N₅O₃S, 541.7; m/z found,542.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ 8.25 (d, J=5.0 Hz,1H), 7.47-7.32 (m, 2H), 7.32-7.22 (m, 1H), 7.19-7.11 (m, 1H), 7.10-6.99(m, 3H), 6.97-6.86 (m, 1H), 5.93 (d, J=4.7 Hz, 1H), 4.06-3.95 (m, 1H),2.96-2.83 (m, 1H), 2.79-2.64 (m, 1H), 2.38-2.25 (m, 2H), 2.15-1.98 (m,5H), 1.86-1.77 (m, 1H), 1.74-1.65 (m, 1H), 1.62-1.53 (m, 1H), 1.53-1.38(m, 3H), 0.84 (t, J=7.0 Hz, 3H).

Example 61:(S)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-1)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps B-I in Example 1, and using2-fluoro-3-methyl-4-nitro-1-phenoxybenzene (Intermediate 18, step B) inplace of 2-methyl-4-phenoxyaniline in step B, and using(3S)-tetrahydropyran-3-amine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₃FN₄O₄S, 518.6; m/z found, 519.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.27 (d, J=5.0 Hz, 1H), 7.42-7.27(m, 2H), 7.25-7.16 (m, 1H), 7.14-6.98 (m, 4H), 6.03 (d, J=5.2 Hz, 1H),392-3.84 (m, 1H), 3.80-3.70 (m, 2H), 3.30-3.12 (m, 2H), 2.02 (s, 3H),1.92-1.83 (m, 1H), 1.67-1.49 (m, 3H).

Example 62:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-ethyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 4-Ethyl-2-methylaniline

To a mixture of 4-bromo-2-methylaniline (1.86 g, 10 mmol), Cs₂CO₃ (10 g,30 mmol), and Pd(dppf)Cl₂ (146 mg, 0.200 mmol) in a Schlenk tube under aN₂ atmosphere was added dry THF (30 mL). To the stirred suspension wasadded trialkylborane (3.0 mL, 1 M in THF, 3.0 mmol) in one portion, andthe mixture was refluxed for 5 h. The reaction was cooled to 0° C. andquenched by the addition of 10% aqueous NaOH and 30% aqueous H₂O₂. Afterstirring for 30 min at rt, the mixture was extracted with EtOAc. Thecombined organic layers were washed with aqueous FeSO₄ and brine, driedover anhydrous Na₂SO₄, filtered, and concentrated to dryness. Theresidue was purified by flash column chromatography to yield the titlecompound (1.1 g, 83% yield) as a white solid.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-ethyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 4-ethyl-2-methylaniline in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₆H₂₇N₅O₃S, 489.6; m/z found, 490.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.23 (s, 1H), 8.30 (d, J=5.5 Hz,1H), 8.08 (s, 1H), 7.36-7.14 (m, 3H), 6.89-6.64 (m, 1H), 6.09 (d, J=16.7Hz, 1H), 5.85 (d, J=5.5 Hz, 1H), 5.67 (d, J=10.5 Hz, 1H), 4.52-4.14 (m,1H), 4.08-3.92 (m, 1H), 3.80-3.60 (m, 1H), 3.15-2.88 (m, 1H), 2.79-2.59(m, 3H), d 2.80-2.60 (m, 3H), 1.99-1.89 (m, 1H), 1.78-1.58 (m, 2H),1.50-1.32 (m, 1H), 1.23 (t, J=7.6 Hz, 3H).

Example 63:(R,E)-N-(1-(2-Cyano-4-methyl-4-(tetrahydro-2H-pyran-4-yl)pent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a sealed tube were added(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 150 mg, 0.27 mmol), 2-methyl-2-morpholinopropanal (65 mg,0.41 mmol), piperidine (30 mg, 0.35 mmol), and EtOH (3 mL) and washeated to 105° C. overnight, cooled to rt, concentrated to dryness, andthe residue purified by flash column chromatography to yield the titlecompound (37 mg, 96% yield) as yellow solid. MS (ESI): mass calcd. forC₃₈H₃₉N₇O₅S, 705.8; m/z found, 706.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.31 (d, J=5.5 Hz, 1H), 7.47-7.36 (m, 2H), 7.35-7.26 (m, 1H), 7.21-7.14(m, 1H), 7.12-7.04 (m, 3H), 7.01-6.93 (m, 1H), 6.89-6.78 (m, 1H),6.08-6.02 m, 1H), 4.52-3.87 (m, 3H), 3.80-3.61 (m, 4H), 3.52-3.35 (m,1H), 3.25-2.85 (m, 1H), 2.74-2.51 (m, 4H), 2.15-2.10 (m, 3H), 2.08-1.57(m, 4H), 1.36-1.26 (m, 6H).

Example 64:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(2,6-difluorophenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using 2,6-difluorophenol in place of phenol instep A, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₀H₂₅F₂N₅O₄S,589.6; m/z found, 590.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.29 (d,J=5.6 Hz, 1H), 7.40-7.26 (m, 2H), 7.21-7.10 (m, 2H), 7.04-6.98 (m, 1H),6.95-6.88 (m, 1H), 6.85-6.70 (m, 1H), 6.27-6.12 (m, 1H), 6.05-5.98 (m,1H), 5.78-5.64 (m, 1H), 4.61-3.84 (m, 3H), 3.24-3.07 (m, 1H), 2.98-2.79(m, 1H), 2.15-2.10 (m, 3H), 2.09-1.98 (m, 1H), 1.94-1.48 (m, 3H).

Example 65:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsD-I in Example 1, and using2-chloro-4-(2-methyl-4-tetrahydropyran-4-yloxyanilino)pyridine-3-carbonitrile(Intermediate 31) in place of2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrile in step D,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₉H₃₁N₅O₅S,561.7; m/z found, 562.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.31-8.27 (m,1H), 7.25-7.20 (m, 1H), 7.05-7.01 (m, 1H), 6.99-6.95 (m, 1H), 6.81-6.77(m, 1H), 6.22-6.17 (m, 1H), 6.04-6.00 (m, 1H), 5.74-5.69 (m, 1H),4.68-4.58 (m, 1H), 4.33-4.11 (m, 1H), 4.07-3.85 (m, 4H), 3.65-3.57 (m,2H), 3.21-3.18 (m, 1H), 2.93-2.86 (m, 1H), 2.11 (s, 3H), 2.09-2.02 (m,3H), 1.89-1.83 (m, 1H), 1.80-1.69 (m, 3H), 1.55-1.50 (m, 1H).

Example 66:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-ethoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 4-Ethoxy-2-methyl-1-nitrobenzene

To a mixture of 3-methyl-4-nitrophenol (5.0 g, 33 mmol) and K₂CO₃ (13.6g, 98.6 mmol) in DMF (25 mL) was added bromoethane (8.9 g, 82 mmol) andthe reaction was stirred at 80° C. overnight. Water was added to thereaction mixture and a yellow solid was precipitated. The precipitatewas filtered, washed with water, and dried to yield the title compound(4.5 g, 76% yield) as a yellow solid.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-ethoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsB-I in Example 1, using 4-ethoxy-2-methyl-1-nitrobenzene in place of2-methyl-1-nitro-4-phenoxybenzene in step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₆H₂₇N₅O₄S, 505.6; m/z found, 506.0[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33-8.22 (m, 1H), 7.29-7.16 (m, 1H),7.01-6.88 (m, 2H), 6.87-6.70 (m, 1H), 6.26-6.12 (m, 1H), 6.04-5.94 (m,1H), 5.77-5.65 (m, 1H), 4.57-3.89 (m, 5H), 3.21-3.05 (m, 1H), 2.96-2.77(m, 1H), 2.10 (s, 3H), 2.07-1.99 (m, 1H), 1.88-1.80 (m, 1H), 1.78-1.49(m, 2H), 1.44-1.35 (m, 3H).

Example 67:(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using (3S)-tetrahydropyran-3-amine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₄N₄O₄S,500.6; m/z found, 501.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.23 (s,1H), 8.33 (d, J=5.5 Hz, 1H), 7.96 (d, J=7.4 Hz, 1H), 7.51-7.41 (m, 2H),7.41-7.33 (m, 1H), 7.26-7.16 (m, 1H), 7.15-7.04 (m, 3H), 7.03-6.90 (m,1H), 5.97 (d, J=5.4 Hz, 1H), 4.00-3.84 (m, 1H), 3.84-3.69 (m, 2H),3.25-3.12 (m, 2H), 2.06 (s, 3H), 1.97-1.85 (m, 1H), 1.78-1.50 (m, 3H).

Example 68:(S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G (including Chiral resolution Method A after Step F to obtain the *Satropisomer) in Example 1, and using (3S)-tetrahydrofuran-3-amine inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₆H₂₂N₄O₄S,486.5; m/z found, 487.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.40-8.27 (m,1H), 7.40-7.35 (m, 2H), 7.34-7.24 (m, 1H), 7.23-7.14 (m, 1H), 7.13-7.02(m, 3H), 7.00-6.92 (m, 1H), 6.08 (d, J=4.7 Hz, 1H), 4.65-4.50 (m, 1H),4.06-3.90 (m, 2H), 3.88-3.65 (m, 2H), 2.35-2.21 (m, 1H), 2.13 (s, 3H),2.06-1.95 (m, 1H).

Example 69:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2,6-difluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 1,3-Difluoro-2-nitro-5-phenoxybenzene

3,5-Difluoro-4-nitrophenol (Intermediate 26) (493 mg, 2.82 mmol) wasdissolved in CH₃CN (45 mL, 860 mmol) and (2-trimethylsilylphenyl)trifluoromethanesulfonate (1.0 mL, 4.2 mmol) was added, followed bycesium fluoride (1.28 g, 8.45 mmol). The reaction was stirred at rtovernight under argon. The reaction was washed with saturated aqueousNaCl (50 mL) and the aqueous phase was extracted with Et₂O (50 mL). Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated to dryness. The product was purified by flash columnchromatography to yield the title compound (450.7 mg, 63.70% yield) as ayellow oil.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2,6-difluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsB-I in Example 1, using 1,3-difluoro-2-nitro-5-phenoxybenzene in placeof 2-methyl-4-phenoxyaniline in step B and tert-butyl(R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₉H₂₃F₂N₅O₄S, 575.6; m/z found, 576.3[M+H]⁺. 1H NMR (400 MHz, CDCl₃) δ9.51 (s, 1H), 8.43 (d, J=5.05 Hz, 1H),7.46 (t, J=7.83 Hz, 2H), 7.28-7.31 (m, 1H), 7.12-7.16 (m, 2H), 6.69 (d,J=9.09 Hz, 2H), 6.62 (dd, J=16.67, 10.61 Hz, 1H), 6.25-6.51 (m, 1H),6.16-6.24 (m, 1H), 5.70-5.82 (m, 1H), 5.38-5.52 (m, 1H), 3.87-4.22 (m,2H), 3.27-3.77 (m, 3H), 1.87-2.13 (m, 2H), 1.62-1.85 (m, 2H).

Example 70:(R)-5-(4-(Benzofuran-7-yloxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using benzofuran-7-ol (Intermediate 8) in place ofphenol in step A, and using (3R)-1-methylpiperidin-3-amine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₄S,553.6; m/z found, 554.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.41 (s, 1H),8.35-8.29 (m, 1H), 7.77-7.72 (m, 1H), 7.51-7.45 (m, 1H), 7.31-7.22 (m,2H), 7.07-7.02 (m, 2H), 6.98-6.93 (m, 1H), 6.92-6.88 (m, 1H), 6.10-6.05(m, 1H), 4.33-4.18 (m, 1H), 3.47-3.36 (m, 1H), 3.26-3.14 (m, 1H),2.91-2.68 (m, 5H), 2.10 (s, 3H), 2.06-1.96 (m, 2H), 1.89-1.74 (m, 1H),1.73-1.59 (m, 1H).

Example 71:(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps B-I in Example 1, and using2-fluoro-3-methyl-4-nitro-1-phenoxybenzene (Intermediate 18, step B) inplace of 2-methyl-4-phenoxyaniline in step B, and using(3R)-tetrahydropyran-3-amine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₃FN₄O₄S, 518.6; m/z found, 519[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ 8.27 (d, J=5.5 Hz, 1H),7.42-7.28 (m, 2H), 7.23-7.15 (m, 1H), 7.13-6.96 (m, 4H), 6.03 (d, J=5.5Hz, 1H), 3.93-3.83 (m, 1H), 3.80-3.69 (m, 2H), 3.28-3.12 (m, 2H), 2.02(s, 3H), 1.92-1.84 (m, 1H), 1.66-1.50 (m, 3H).

Example 72:(R)—N-(1-(3-Methoxypropanoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the method in Example 104, andusing 3-methoxypropanoic acid in place of 3-methylsulfonylpropanoicacid. MS (ESI): mass calcd. for C₃₀H₂₉N₅O₅S, 571.6; m/z found, 572.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d, J=5.6, 1H), 7.43-7.35 (m,2H), 7.33-7.25 (m, 1H), 7.21-7.12 (m, 1H), 7.12-7.03 (m, 3H), 7.01-6.92(m, 1H), 6.07 (d, J=5.6, 1H), 4.66-4.53 (m, 1H), 3.82-3.70 (m, 1H),3.68-3.60 (m, 3H), 3.56-3.38 (m, 2H), 3.34-3.30 (m, 3H), 2.62-2.54 (m,2H), 2.35-2.17 (m, 1H), 2.16-1.99 (m, 4H).

Example 73:(R)-5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 67, 200 mg, 0.45 mmol) in DCM (50 mL) was added adrop of DMF and then oxalyl chloride (284 mg, 2.24 mmol). The reactionwas stirred at rt for 3 h, concentrated to dryness, and diluted in DCM.Triethylamine (226 mg, 2.24 mmol) and tert-butyl(3R)-3-aminopiperidine-1-carboxylate (107 mg, 0.536 mmol) were added,stirred at rt for 1 h, concentrated to dryness, and purified by flashcolumn chromatography to a yellow solid. The solid was diluted in MeOH,concentrated HCl was added and the solution was concentrated to drynessto yield the title compound (150 mg, 59% yield) as a yellow solid.

Step B:(R)-5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a mixture of(R)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(98 mg, 0.17 mmol) and formaldehyde (0.5 mL, 37 wt. % in H₂O) in MeOH(15 mL) was added NaBH(OAc)₃ (110 mg, 0.52 mmol), then stirred at rt for1 h, concentrated to dryness, and purified by flash columnchromatography to yield the title compound as a white solid (52 mg, 56%yield). MS (ESI): mass calcd. for C₂₉H₂₉N₅O₄S, 543.6; m/z found, 544.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 8.29 (d, J=5.3 Hz, 1H), 8.08 (d,J=7.5 Hz, 1H), 7.28-7.20 (m, 2H), 7.16-7.08 (m, 1H), 7.05-6.97 (m, 1H),6.96-6.86 (m, 1H), 6.82-6.68 (m, 1H), 5.88 (d, J=5.3 Hz, 1H), 3.42-3.90(m, 1H), 3.78 (s, 3H), 2.97-2.85 (m, 1H), 2.81-2.66 (m, 1H), 2.28 (s,3H), 2.11-1.95 (m, 5H), 1.82-1.65 (m, 2H), 1.61-1.48 (m, 1H), 1.46-1.30(m, 1H).

Example 74:(R)—N-(1-Ethylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.30 mmol) in DCM (10 mL) was added acetaldehyde(99 mg, 2.3 mmol). After stirring at rt for 10 min, NaBH(OAc)₃ (190 mg,0.90 mmol) was added. The mixture was stirred at rt overnight and the pHwas adjusted to pH>7 with 2 M aqueous NaOH. The reaction mixture wasconcentrated to dryness and the residue was purified using flash columnchromatography to yield the title compound (44 mg, 27% yield) as ayellow solid. MS (ESI): mass calcd. for C₂₉H₂₉N₅O₃S, 527.6; m/z found,528.2 [M+H]⁺. ¹H NMR (400 MHz, a mixture of DMSO-d6 and CD3OD): δ 8.23(d, J=5.4 Hz, 1H), 7.42-7.31 (m, 2H), 7.30-7.20 (m, 1H), 7.16-7.10 (m,1H), 7.08-7.98 (m, 3H), 6.95-6.83 (m, 1H), 5.91 (d, J=5.4 Hz, 1H),4.03-3.95 (m, 1H), 2.99-2.88 (m, 1H), 2.78-2.71 (m, 1H), 2.46-2.38 (m,2H), 2.09-1.97 (m, 5H), 1.85-1.75 (m, 1H), 1.75-1.65 (m, 1H), 1.60-1.48(m, 1H), 1.46-1.38 (m, 1H), 1.01 (t, J=7.1 Hz, 3H).

Example 75:(R)—N-(1-(3-Hydroxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 120 mg, 0.22 mmol), 3-hydroxypropanoic acid (40 mg, 0.45mmol), HATU (110 mg, 0.29 mmol), diisopropylethylamine (58 mg, 0.45mmol) in DMF (5 mL) was stirred at rt for 2 h. The reaction was purifiedby HPLC to yield the title compound (58 mg, 44% yield) as white solid.MS (ESI): mass calcd. for C₃₀H₂₉N₅O₅S, 571.6; m/z found, 572.4 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ 8.34-8.25 (m, 1H), 7.43-7.35 (m, 2H),7.35-7.28 (m, 1H), 7.19-7.12 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.93 (m,1H), 6.09-6.02 (m, 1H), 4.54-4.03 (m, 2H), 3.98-3.78 (m, 3H), 3.18-3.00(m, 1H), 2.88-2.46 (m, 3H), 2.11 (s, 3H), 2.08-1.98 (m, 1H), 1.90-1.78(m, 1H), 1.76-1.60 (m, 1H), 1.62-1.45 (m, 1H).

Example 76:(R,E)-N-(1-(2-Cyano-3-cyclopropylacrylol)piperidin-3-yl)-5-(4-(2-ethylphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:R)-5-(4-(2-Ethylphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 2-ethylphenol in place of phenol in step A,and using tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(2-ethylphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a mixture of(R)-5-(4-(2-ethylphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(70 mg, 0.13 mmol) and triethylamine (28 mg, 0.28 mmol) in DMF (2 mL)were added (E)-2-cyano-3-cyclopropylprop-2-enoic acid (Intermediate 17)(36 mg, 0.26 mmol) and HATU (100 mg, 0.27 mmol) and was reacted at rtfor 20 min. The reaction was quenched with H₂O (10 mL), extracted withDCM, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness.The residue was purified by flash column chromatography to obtain thetitle compound (60 mg, 97% yield) as a white solid. MS (ESI): masscalcd. for C₃₆H₃₄N₆O₄S, 646.8; m/z found, 647.0 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.37-8.29 (m, 1H), 7.35-7.29 (m, 1H), 7.27-7.20 (m, 2H),7.18-7.12 (m, 1H), 7.00-6.93 (m, 2H), 6.88-6.83 (m, 1H), 6.57-6.47 (m,1H), 6.07-6.03 (m, 1H), 4.33-4.06 (m, 1H), 4.15-3.93 (m, 2H), 3.28-2.98(m, 2H), 2.68-2.59 (m, 2H), 2.10 (s, 3H), 2.08-1.94 (m, 2H), 1.92-1.85(m, 1H), 1.84-1.56 (m, 2H), 1.27-1.56 (m, 5H), 1.07-1.78 (m, 2H).

Example 77:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2,3-dimethyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using 1-fluoro-2,3-dimethyl-4-nitrobenzene inplace of 5-fluoro-2-nitrotoluene in step A, and using tert-butyl(R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₄S, 553.6; m/z found, 554.3[M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ 8.26-8.11 (br, 1H),7.34-7.28 (m, 2H), 7.09 (d, J=8.3 Hz, 1H), 7.06-7.00 (m, 1H), 6.95-6.88(m, 2H), 6.84 (d, J=8.6 Hz, 1H), 6.60-6.47 (m, 1H), 6.17-6.10 (m, 1H),5.94-5.79 (m, 1H), 5.66-5.60 (m, 1H), 4.55-4.44 (m, 1H), 3.75-3.67 (m,1H), 3.64-3.57 (m, 1H), 3.55-3.45 (m, 1H), 3.45-3.36 (m, 1H), 2.16 (s,3H), 2.15-2.06 (m, 1H), 2.01 (s, 3H), 1.96-1.91 (m, 1H).

Example 78:(R)—N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 120 mg, 0.22 mmol) in DMF (2 mL) was added2-(dimethylamino)acetic acid (47 mg, 0.34 mmol), HATU (102 mg, 0.268mmol), and triethylamine (0.128 mL, 0.896 mmol). The mixture was stirredat rt overnight, then purified by flash column chromatography to yieldthe title compound (36 mg, 26% yield) as a yellow solid. MS (ESI): masscalcd. for C₃₁H₃₂N₆O₄S, 584.7; m/z found, 585.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.26 (d, J=5.5, 1H), 7.45-7.35 (m, 2H), 7.32-7.23 (m, 1H),7.20-7.12 (m, 1H), 7.11-7.00 (m, 3H), 7.00-6.90 (m, 1H), 6.00 (d, J=4.9,1H), 4.06-3.91 (m, 2H), 3.79-3.59 (m, 1H), 3.50-3.39 (m, 2H), 3.23-3.06(m, 2H), 2.52-2.31 (m, 6H), 2.10 (s, 3H), 2.06-1.97 (m, 1H), 1.79-1.89(m, 1H), 1.74-1.49 (m, 2H).

Example 79:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-fluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-Fluoro-1-nitro-4-phenoxybenzene

To a mixture of 3-fluoro-4-nitrophenol (2.0 g, 13 mmol), phenylboronicacid (2.33 g, 19.1 mmol), Cu(OAc)₂ (4.6 g, 25 mmol), and triethylamine(6.4 g, 64 mmol) in DCM (60 mL) was added molecular sieves (4A powder<50μm, 2 g). The mixture was stirred at rt under N₂ overnight, filtered,concentrated to dryness, and purified by flash column chromatography toyield the title compound (2.7 g, 91% yield) as a yellow solid.

Step B:(R)-5-(2-Fluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsB-H in Example 1, and using 2-fluoro-1-nitro-4-phenoxybenzene in placeof_2-methyl-1-nitro-4-phenoxybenzene in step B and tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step C:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-fluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-fluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(150 mg, 0.30 mmol), (E)-2-cyano-3-cyclopropylprop-2-enoic acid(Intermediate 17) (61 mg, 45 mmol), HATU (2.27 g, 5.96 mmol), andtriethylamine (150 mg, 1.5 mmol) in DMF (4 mL) was stirred at rt for 2h, then purified by flash column chromatography to yield the titlecompound (124 mg, 67% yield) as a white solid. MS (ESI): mass calcd. forC₃₃H₂₇FN₆O₄S, 622.7; m/z found, 623.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6):δ 8.32 (d, J=5.5 Hz, 1H), 8.21 (s, 1H), 7.62-7.50 (m, 1H), 7.50-7.39 (m,2H), 7.28-7.19 (m, 1H), 7.19-7.08 (m, 3H), 6.99-6.89 (m, 1H), 6.66-6.47(m, 1H), 6.15 (d, J=5.4 Hz, 1H), 4.04-4.00 (m, 1H), 3.99-3.72 (m, 2H),3.10-2.68 (m, 2H), 2.00-1.71 (m, 3H), 1.70-1.58 (m, 1H), 1.56-1.37 (m,1H), 1.18-1.05 (m, 2H), 1.02-0.68 (m, 2H).

Example 80:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-1)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 16) (30 mg, 0.072 mmol), HATU (55 mg, 0.15 mmol), andtriethylamine (22 mg, 0.22 mmol) in anhydrous DMF (3 mL) was stirred atrt. After 10 min, (3R)-tetrahydrofuran-3-amine (10 mg, 0.12 mmol) wasadded and the mixture was stirred for 2 h. The crude mixture waspurified by flash column chromatography to yield the title compound (27mg, 99% yield) as a slight yellow solid. MS (ESI): mass calcd. forC₂₆H₂₂N₄O₄S, 486.5; m/z found, 487.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.33 (d, J=5.5 Hz, 1H), 7.46-7.35 (m, 2H), 7.29 (d, J=8.6 Hz, 1H),7.21-7.13 (m, 1H), 7.12-7.03 (m, 3H), 7.00-6.94 (m, 1H), 6.07 (d, J=5.5Hz, 1H), 4.65-4.53 (m, 1H), 4.03-3.88 (m, 2H), 3.87-3.76 (m, 1H),3.75-3.66 (m, 1H), 2.36-2.22 (m, 1H), 2.12 (s, 3H), 2.06-1.97 (m, 1H).

Example 81:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2,6-dimethyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, using 5-fluoro-1,3-dimethyl-2-nitrobenzene in place of5-fluoro-2-nitrotoluene in step A and tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₄S, 553.6; m/z found, 554.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ 8.36-8.27 (m, 1H),7.41-7.31 (m, 2H), 7.17-7.10 (m, 1H), 7.08-7.01 (m, 2H), 6.84 (s, 2H),6.61-6.48 (m, 1H), 6.20-6.13 (m, 1H), 5.98-5.92 (m, 1H), 5.69-5.61 (m,1H), 4.59-4.46 (m, 1H), 3.96-3.84 (m, 1H), 3.75-3.69 (m, 1H), 3.63-3.45(m, 2H), 2.27-2.02 (m, 2H), 2.01 (s, 6H).

Example 82:(S)—N-(1-acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1 (including Chiral resolution Method A after Step F toobtain the *S atropisomer), and using tert-butyl(3S)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₄S, 553.6; m/z found, 554.2[M+H]+. ¹H NMR (400 MHz, CD₃OD): δ 8.34-8.22 (m, 1H), 7.45-7.36 (m, 2H),7.33-7.23 (m, 1H), 7.21-7.13 (m, 1H), 7.13-7.03 (m, 3H), 7.01-6.93 (m,1H), 6.87-6.72 (m, 1H), 6.29-6.14 (m, 1H), 6.08-5.96 (m, 1H), 5.79-5.68(m, 1H), 4.53-3.95 (m, 3H), 3.28-3.10 (m, 1H), 3.04-2.84 (m, 1H),2.15-2.02 (m, 4H), 1.96-1.83 (m, 1H), 1.82-1.68 (m, 1H), 1.63-1.49 (m,1H).

Example 83:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pentafluorothio)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-Methyl-4-(pentafluorosulfanyl)aniline

To a stirred solution of 2-methyl-4-(pentafluorosulfanyl)nitrobenzene(1.5 g, 5.7 mmol) in ethanol (50 mL) was added Fe powder (1.28 g, 22.8mmol), followed by the slow addition of concentrated HCl (2.5 mL) at 0°C. The mixture was stirred at rt for 1 h and the reaction was quenchedby pouring into ice water and neutralized with sodium carbonate. Thereaction was extracted with DCM, dried over anhydrous Na₂SO₄, filtered,and concentrated to dryness to yield the title compound (1.13 g, 85%yield) as a yellow oil.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pentafluorothio)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-G in Example 1, and using 2-methyl-4-(pentafluorosulfanyl)aniline inplace of 2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₄H₂₂F₅N₅O₃S₂,587.6; m/z found, 588.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.36-8.28 (m,1H), 8.02-7.96 (m, 1H), 7.93-7.85 (m, 1H), 7.66-7.58 (m, 1H), 6.85-6.73(m, 1H), 6.25-6.15 (m, 1H), 6.06-6.00 (m, 1H), 5.79-5.68 (m, 1H),4.59-3.89 (m, 3H), 3.25-3.12 (m, 1H), 3.00-2.84 (m, 1H), 2.28 (s, 3H),2.12-1.99 (m, 1H), 1.92-1.82 (m, 1H), 1.80-1.66 (m, 1H), 1.66-1.53 (m,1H).

Example 84:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 36, 60 mg, 0.12 mmol), DCM (2 mL), and triethylamine (30mg, 0.3 mmol) was added propanoyl propanoate (39 mg, 0.3 mmol) in DCM (2mL) dropwise and stirred at room temperature for 2 h. The reactionmixture was concentrated to dryness and purified by normal phase flashcolumn chromatography (SiO₂), then by preparative TLC to yield the titlecompound (27 mg, 42%) as a yellow solid. MS (ESI): mass calcd. forC₂₉H₂₇N₅O₄S, 541.6; m/z found, 542.2 [M+H]+. ¹H NMR (400 MHz, CDCl₃): δ9.45 (s, 1H), 8.39-8.33 (m, 1H), 7.43-7.34 (m, 2H), 7.21-7.13 (m, 2H),7.13-7.07 (m, 2H), 7.03-7.00 (m, 1H), 6.98-6.93 (m, 1H), 6.06-6.00 (m,1H), 5.76-5.63 (m, 1H), 4.73-4.59 (m, 1H), 3.91-3.78 (m, 1H), 3.74-3.35(m, 3H), 2.41-2.20 (m, 3H), 2.14-2.10 (m, 3H), 2.09-1.86 (m, 1H),1.22-1.13 (m, 3H).

Example 85: (R)-Tetrahydro-2H-pyran-3-yl5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

To a solution of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27, 150 mg, 0.36 mmol) in DCM (60 mL) was added adrop of DMF, then oxalyl chloride (230 mg, 1.8 mmol) was added. Thereaction was stirred at rt for 3 h, concentrated to dryness, and dilutedin DCM. Next, triethylamine (180 mg, 1.8 mmol) and(3R)-tetrahydropyran-3-amine (54 mg, 0.54 mmol) were added and thereaction was stirred at rt for 1 h, then concentrated to dryness, andpurified by flash column chromatography to yield the title compound (115mg, 64.1% yield) as a white solid. MS (ESI): mass calcd. forC₂₇H₂₄N₄O₄S, 500.6; m/z found, 501.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6):δ 8.31 (d, J=5.5 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.50-7.38 (m, 2H),7.37-7.30 (m, 1H), 7.24-7.15 (m, 1H), 7.15-7.03 (m, 3H), 7.00-6.92 (m,1H), 5.95 (d, J=5.4 Hz, 1H), 3.94-3.85 (m, 1H), 3.85-3.70 (m, 2H),3.25-3.12 (m, 2H), 2.04 (s, 3H), 1.96-1.85 (m, 1H), 1.73-1.51 (m, 3H).

Example 86:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2,4-dimethylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:5-(2,4-Dimethylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared in a manner analogous to Method 1, stepsC-F in Example 1, and using 2,4-dimethylaniline in place of2-methyl-4-phenoxyaniline in step C.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2,4-dimethylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of5-(2,4-dimethylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (200 mg, 0.59 mmol) and 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one(Intermediate 15, 300 mg, 1.9 mmol) in anhydrous DMF were added HATU(570 mg, 1.5 mmol) and diisopropylethylamine (260 mg, 2.0 mmol) and themixture stirred overnight at rt. The reaction mixture was purified byflash column chromatography, then preparative TLC to yield the titlecompound as a yellow solid. MS (ESI): mass calcd. for C₂₅H₂₅N₅O₃S,475.6; m/z found, 476.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.31-10.12(m, 1H), 8.30 (d, J=5.5 Hz, 1H), 8.14-8.00 (m, 1H), 7.28-7.25 (m, 1H),7.25-7.17 (m, 2H), 6.85-6.69 (m, 1H), 6.14-6.02 (m, 1H), 5.86 (d, J=5.5Hz, 1H), 5.71-5.62 (m, 1H), 4.51-4.14 (m, 1H), 4.07-3.91 (m, 1H),3.83-3.69 (m, 1H), 3.13-2.91 (m, 1H), 2.79-2.60 (m, 1H), 2.35 (s, 3H),2.04 (s, 3H), 1.97-1.87 (m, 1H), 1.81-1.71 (m, 1H), 1.71-1.56 (m, 1H),1.50-1.32 (m, 1H).

Example 87:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1 (including Chiral resolution Method A after Step F toobtain the *R atropisomer), and using tert-butyl(R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₄S, 553.6; m/z found, 554.3[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d, J=5.6 Hz, 1H), 7.49-7.36 (m,2H), 7.30 (d, J=8.6 Hz, 1H), 7.22-7.16 (m, 1H), 7.13-7.02 (m, 3H),7.00-6.93 (m, 1H), 6.87-6.70 (m, 1H), 6.25-6.13 (m, 1H), 6.07 (d, J=5.5Hz, 1H), 5.79-5.67 (m, 1H), 4.57-3.89 (m, 3H), 3.25-3.10 (m, 1H),2.99-2.80 (m, 1H), 2.12 (s, 3H), 2.08-2.00 (m, 1H), 1.94-1.82 (m, 1H),1.79-1.66 (m, 1H), 1.65-1.52 (m 1H).

Example 88:(S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1 (including Chiral resolution Method A after Step F toobtain the *S atropisomer), and using (S)-tetrahydro-2H-pyran-3-amine inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate instep G. MS (ESI): mass calcd. for C₂₇H₂₄N₄O₄S, 500.6; m/z found, 501.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ 8.27 (d, J=5.5 Hz, 1H),7.43-7.32 (m, 2H), 7.27 (d, J=8.6 Hz, 1H), 7.17-7.09 (m, 1H), 7.08-6.97(m, 3H), 6.95-6.86 (m, 1H), 5.96 (d, J=5.5 Hz, 1H), 3.96-3.87 (m, 1H),3.84-3.78 (m, 1H), 3.77-3.69 (m, 1H), 3.33-3.25 (m, 1H), 3.24-3.15 (m,1H), 2.04 (s, 3H), 1.98-1.87 (m, 1H), 1.70-1.54 (m, 3H).

Example 89:(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenl)-N-(1-(3-methoxypropanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 18) (80 mg, 0.16 mmol), 3-methoxypropanoic acid (32 mg,0.31 mmol), triethylamine (31 mg, 0.31 mmol), and HATU (118 mg, 0.310mmol) in DMF (2 mL) was stirred at rt for 1 hr. Water was added and theprecipitate was filtered to give a crude product, which was purified byflash column chromatography to yield the title compound (73 mg, 77%yield) as a white solid. MS (ESI): mass calcd. for C₃₁H₃₀FN₅O₅S, 603.7;m/z found, 604.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.39-8.26 (m, 1H),7.45-7.31 (m, 2H), 7.24-7.18 (m, 1H), 7.17-7.10 (m, 1H), 7.09-7.02 (m,3H), 6.16-6.07 (m, 1H), 4.53-4.29 (m, 1H), 4.13-3.85 (m, 2H), 3.70-3.60(m, 2H), 3.32 (s, 3H), 3.17-2.98 (m, 1H), 2.86-2.63 (m, 3H), 2.12 (s,3H), 2.07-1.97 (m, 1H), 1.88-1.75 (m, 1H), 1.1.73-1.46 (m, 2H).

Example 90:(S)-5-(2-Methyl-4-phenoxyphenl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27, 100 mg, 0.24 mmol) in DCM (25 mL) was added adrop of DMF, then oxalyl chloride (150 mg, 1.2 mmol) was added. Thereaction was stirred at rt for 3 h, concentrated to dryness, and dilutedin DCM again. Next, triethylamine (120 mg, 1.2 mmol) and(3S)-tetrahydrofuran-3-amine (31 mg, 0.36 mmol) were added and stirredat rt for 1 h. The reaction mixture was concentrated dryness andpurified by flash column chromatography to yield the title compound (60mg, 51% yield) as a yellow solid. MS (ESI): mass calcd. for C₂₆H₂₂N₄O₄S,486.5; m/z found, 487.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.25 (s,1H), 8.37-8.27 (m, 2H), 7.49-7.39 (m, 2H), 7.37 (d, J=8.6 Hz, 1H),7.24-7.15 (m, 1H), 7.13-7.04 (m, 3H), 7.02-6.93 (m, 1H), 5.96 (d, J=5.5Hz, 1H), 4.52-4.37 (m, 1H), 3.90-3.78 (m, 2H), 3.74-3.65 (m, 1H),3.63-3.57 (m, 1H), 2.20-2.08 (m, 1H), 2.05 (s, 3H), 1.98-1.87 (m, 1H).

Example 91:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butylmethyl(2-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-2-oxoethyl)carbamate

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 200 mg, 0.40 mmol) in DMF (3 mL) were added2-[tert-butoxycarbonyl(methyl)amino]acetic acid (Intermediate 21, 114mg, 0.603 mmol), HATU (230 mg, 0.60 mmol), and triethylamine (0.23 mL,1.6 mmol). The mixture was stirred at rt overnight, then purified byflash column chromatography to yield the title compound (198 mg, 73.0%yield) as a yellow solid.

Step B:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added (R)-tert-butylmethyl(2-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-2-oxoethyl)carbamate(198 mg, 0.300 mmol) and HCl in MeOH (3 M, 3 mL) and was stirred at rtfor 4 h, then the pH was adjusted to pH>7 with 2 M aqueous NaOH. Themixture was purified by flash column chromatography to yield the titlecompound as a yellow solid (95 mg, 56% yield). MS (ESI): mass calcd. forC₃₀H₃₀N₆O₄S, 570.7; m/z found, 571.2 [M+H]⁺. ¹H NMR (400 MHz, a mixturesolution of DMSO-d₆ and CD₃OD): δ 8.02-7.98 (m, 1H), 7.39-7.32 (m, 2H),7.14-7.08 (m, 2H), 7.07-7.01 (m, 2H), 6.99-6.96 (m, 1H), 6.92-6.84 (m,1H), 5.69-5.62 (m, 1H), 4.10-3.92 (m, 1H), 3.92-3.83 (m, 1H), 3.72-3.52(m, 2H), 3.52-3.36 (m, 2H), 3.32-3.21 (m, 1H), 2.31-2.23 (m, 3H), 2.01(s, 3H), 1.95-1.86 (m, 1H), 1.81-1.59 (m, 2H), 1.54-1.41 (m, 1H).

Example 92:N-(1,6-Dimethylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A mixtureof-(2-Methyl-4-phenoxyphenyl)-N-((6R)-6-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 173, 150 mg, 0.29 mmol), NaBH(OAc)₃ (123 mg, 0.580 mmol), andformaldehyde (1 mL, 37 wt. % in H₂O) in DCM (5 mL) was reacted at 80° C.for 2 h. The reaction mixture was concentrated to dryness, saturatedaqueous NaHCO₃ was added, extracted with DCM, dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby flash column chromatography to yield the title compound as a yellowsolid. MS (ESI): mass calcd. for C₂₉H₂₉N₅O₃S, 527.6; m/z found, 528.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.42 (s, 1H), 8.37-8.30 (m, 1H),7.45-7.37 (m, 2H), 7.33-7.26 (m, 1H), 7.21-7.14 (m, 1H), 7.11-7.02 (m,3H), 7.00-6.92 (m, 1H), 6.12-6.05 (m, 1H), 4.36-4.23 (m, 1H), 3.63-3.56(m, 1H), 3.06-2.95 (m, 1H), 2.89-2.79 (m, 4H), 2.11 (s, 3H), 2.12-1.99(m, 2H), 1.81-1.63 (m, 2H), 1.41-1.32 (m, 3H).

Example 93:(R)—N-(1-Isopropylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 36, 60 mg, 0.12 mmol) dissolved in acetone was stirred for10 min, then NaBH(OAc)₃ (100 mg, 0.5 mmol) was added slowly and themixture was stirred for 2 h. Next, NaOH (2 mL) was added and the mixturewas purified by flash column chromatography, then preparative TLC toyield the title compound as a yellow solid (11 mg, 17%). MS (ESI): masscalcd. for C₂₉H₂₉N₅O₃S, 527.6; m/z found, 528.2 [M+H]⁺. −H NMR (400 MHz,DMSO-d6): δ 8.42 (s, 1H), 8.25 (d, J=5.4 Hz, 1H), 7.47-7.39 (m, 2H),7.33-7.27 (m, 1H), 7.21-7.15 (m, 1H), 7.12-7.08 (m, 2H), 7.07-7.04 (m,1H), 6.98-6.92 (m, 1H), 5.87 (d, J=5.4 Hz, 1H), 4.45-4.31 (m, 1H),2.95-2.75 (m, 2H), 2.64-2.55 (m, 2H), 2.20-2.09 (m, 1H), 2.03 (s, 3H),2.01-1.92 (m, 1H), 1.84-1.73 (m, 1H), 1.09-1.00 (m, 6H).

Example 94:N-((3S,4R)-4-Fluoro-1-(3-methoxypropanoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:N-((3S,4R)-4-Fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:N-((3S,4R)-4-Fluoro-1-(3-methoxypropanoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A mixture ofN-((3S,4R)-4-fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(80 mg, 0.16 mmol), 3-methoxypropanoic acid (33 mg, 0.32 mmol),triethylamine (32 mg, 0.32 mmol), and HATU (120 mg, 0.32 mmol) in DMF (3mL) was stirred at rt for 1 h, then water was added and the precipitatewas collected by filtration and purified by flash column chromatographyto yield the title compound as a white solid (75 mg, 78% yield). MS(ESI): mass calcd. for C₃₀H₂₈FN₅O₅S, 589.6; m/z found, 590.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.33 (d, J=5.3 Hz, 1H), 7.43-7.34 (m, 2H),7.34-7.26 (m, 1H), 7.20-7.12 m, 1H), 7.12-7.02 (m, 3H), 6.99-6.94 (m,1H), 6.07 (d, J=5.2 Hz, 1H), 5.36-5.14 (m, 1H), 4.80-4.63 (m, 1H),4.07-3.45 (m, 6H), 3.33 (s, 3H), 2.68-2.51 (m, 2H), 2.11 (s, 3H).

Example 95:(R)—N-(1-(2-Methoxyacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 120 mg, 0.22 mmol) in DMF (2 mL) were added2-methoxyacetic acid (0.026 mL, 0.34 mmol), HATU (100 mg, 0.27 mmol),and DMF (2 mL). The mixture was stirred at rt overnight, then purifiedby flash column chromatography to yield the title compound as a yellowsolid (83 mg, 63%). MS (ESI): mass calcd. for C₃₀H₂₉N₅O₅S, 571.6; m/zfound, 572.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d, J=5.5, 1H),7.45-7.35 (m, 2H), 7.33-7.27 (m, 1H), 7.20-7.12 (m, 1H), 7.12-7.02 (m,3H), 7.02-6.93 (m, 1H), 6.07 (d, J=5.3, 1H), 4.29-4.09 (m, 3H),4.02-3.85 (m, 2H), 3.39 (s, 3H), 3.11-3.01 (m, 1H), 2.86-2.74 (m, 1H),2.11 (s, 3H), 2.09-2.00 (m, 1H), 1.88-1.78 (m, 1H), 1.76-1.52 (m, 2H).

Example 96:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 16) (30 mg, 0.07 mmol), HBTU (55 mg, 0.15 mmol), andtriethylamine (22 mg, 0.22 mmol) in anhydrous DMF (3 mL) was stirred atrt. After 10 min, (3R)-tetrahydropyran-3-amine (11 mg, 0.11 mmol) wasadded and the mixture was stirred for 2 h at rt. The crude mixture waspurified by flash column chromatography to yield the title compound as aslight yellow solid (25 mg, 69% yield). MS (ESI): mass calcd. forC₂₇H₂₄N₄O₄S, 500.6; m/z found, 501.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD andDMSO-d₆): δ 8.28 (d, J=5.5 Hz, 1H), 7.41-7.33 (m, 2H), 7.28 (d, J=8.7Hz, 1H), 7.18-7.10 (m, 1H), 7.09-6.97 (m, 3H), 6.96-6.86 (m, 1H), 5.96(d, J=5.5 Hz, 1H), 3.98-3.91 (m, 1H), 3.85-3.69 (m, 2H), 3.35-3.24 (m,1H), 3.25-3.17 (m, 1H), 2.04 (s, 3H), 1.96-1.87 (m, 1H), 1.74-1.53 (m,3H).

Example 97:N-(1-Cyanoazepan-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl 3-aminoazepane-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, and using bromocyanide in place ofprop-2-enoyl chloride in step I. MS (ESI): mass calcd. for C₂₉H₂₆N₆O₃S,538.6; m/z found, 539.6 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ8.28 (d, J=5.5 Hz, 1H), 7.41-7.32 (m, 2H), 7.28 (d, J=8.6 Hz, 1H),7.16-7.08 (m, 1H), 7.09-6.99 (m, 3H), 6.94-6.90 (m, 1H), 5.99 (d, J=5.5Hz, 1H), 4.18-4.09 (m, 1H), 3.48-3.37 (m, 1H), 3.36-3.27 (m, 1H),3.25-3.17 (m, 2H), 2.05 (s, 3H), 1.95-1.80 (m, 3H), 1.72-1.60 (m, 2H),1.55-1.42 (m, 1H).

Example 98:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1 (including Chiral resolution Method A after Step F toobtain the *S atropisomer), and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.2[M+H]+. ¹H NMR (400 MHz, CD₃OD): δ 8.20 (d, J=5.6 Hz, 1H), 7.48-7.34 (m,2H), 7.27-7.21 (m, 1H), 7.19-7.13 (m, 1H), 7.11-7.03 (m, 3H), 7.00-6.94(m, 1H), 5.94 (d, J=5.6 Hz, 1H), 4.19-4.06 (m, 1H), 3.29-3.21 (m, 1H),3.15-3.00 (m, 1H), 2.89-2.70 (m, 2H), 2.11 (s, 3H), 2.08-1.86 (m, 2H),1.79-1.64 (m, 2H).

Example 99:(R)—N-(1-(3-Hydroxypropanoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution containing(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98, 39 mg, 0.073 mmol), 3-hydroxypropanoic acid (13 mg, 0.14mmol), HATU (36 mg, 0.095 mmol), and diisopropylethylamine (24 mg, 0.18mmol) in DMF (5 mL) was stirred at rt for 2 h. The mixture was purifiedby flash column chromatography to yield the title compound as a whitesolid (15 mg, 36% yield). MS (ESI): mass calcd. for C₃₀H₂₉N₅O₅S, 571.6;m/z found, 572.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.36-8.30 (m, 1H),7.44-7.37 (m, 2H), 7.33-7.27 (m, 1H), 7.21-7.14 (m, 1H), 7.12-7.03 (m,3H), 7.01-6.95 (m, 1H), 6.11-6.05 (m, 1H), 4.51-3.90 (m, 3H), 3.88-3.79(m, 2H), 3.20-3.05 (m, 1H), 2.90-2.75 (m, 1H), 2.73-2.58 (m, 2H), 2.12(s, 3H), 2.09-2.01 (m, 1H), 1.91-1.77 (m, 1H), 1.77-1.64 (m, 1H),1.64-1.45 (m, 1H).

Example 100:(R,E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98, 45 mg, 0.090 mmol), (E)-but-2-enoic acid (15.5 mg, 0.18mmol), HATU (68 mg, 0.18 mmol), triethylamine (18 mg, 0.18 mmol) in DMF(1 mL) was stirred at rt for 4 h. The mixture was purified by flashcolumn chromatography to yield the title compound as a yellow solid (51mg, 100% yield). MS (ESI): mass calcd. for C₃₁H₂₉N₅O₄S, 567.7; m/zfound, 568.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.21 (br, 1H),8.35-8.26 (m, 1H), 8.22-8.02 (br, 1H), 7.45-7.40 (m, 2H), 7.36-7.31 (m,1H), 7.20-7.16 (m, 1H), 7.12-7.08 (m, 2H), 7.08-7.05 (m, 1H), 6.98-6.93(m, 1H), 6.69-6.59 (m, 1H), 6.55-6.35 (m, 1H), 5.97-5.89 (m, 1H),4.49-4.04 (m, 1H), 4.04-3.90 (m, 1H), 3.77-3.72 (m, 1H), 2.92-2.85 (m,1H), 2.76-2.60 (m, 1H), 2.03 (s, 3H), 1.94-1.88 (m, 1H), 1.83-1.77 (m,3H), 1.76-1.70 (m, 1H), 1.66-1.57 (m, 1H), 1.47-1.37 (s, 1H).

Example 101:(R)—N-(1-Isopropylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A mixture of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.30 mmol) in acetone (10 mL) was stirred at rtfor 10 min, then NaBH(OAc)₃ (190 mg, 0.90 mmol) was added. The mixturewas stirred at rt overnight and adjusted to pH>7 with 2 M aqueous NaOH.The reaction mixture was concentrated to dryness and the residuepurified by flash column chromatography to yield the title compound as ayellow solid (52 mg, 32% yield). MS (ESI): mass calcd. for C₃₀H₃₁N₅O₃S,541.7; m/z found, 542.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ8.23 (d, J=4.7, 1H), 7.43-7.31 (m, 2H), 7.31-7.21 (m, 1H), 7.19-7.11 (m,1H), 7.11-6.97 (m, 3H), 6.96-6.85 (m, 1H), 5.91 (d, J=4.7, 1H),4.04-3.95 (m, 1H), 2.98-2.71 (m, 3H), 2.32-2.19 (m, 2H), 2.03 (s, 3H),1.86-1.77 (m, 1H), 1.77-1.67 (m, 1H), 1.60-1.47 (m, 1H), 1.47-1.37 (m,1H), 1.01 (d, J=5.7, 6H).

Example 102:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 4-Isopropoxy-2-methyl-1-nitrobenzene

To a mixture of 3-methyl-4-nitrophenol (5.0 g, 33 mmol) and K₂CO₃ (9.0g, 65 mmol) in DMF (20 mL) was added 2-iodopropane (8.3 g, 49 mmol) andthe reaction was stirred at 80° C. overnight. Water was added to themixture to yield a precipitate, then filtered, washed with water, anddried to yield the title compound as a yellow solid (5.0 g, 78% yield).

Step B:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a stirred solution of(R)-5-(4-Isopropoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 70, 80 mg, 0.17 mmol) in DMF (3 mL) were added(E)-2-cyano-3-cyclopropylprop-2-enoic acid (Intermediate 17) (28 mg,0.20 mmol), HATU (78 mg, 0.20 mmol), and diisopropylethylamine (0.05 mL)and was stirred at rt overnight. The reaction was concentrated todryness and the residue was partitioned between ethyl acetate and water.The organic layer was separated, shaken with brine, and dried overanhydrous Na₂SO₄. The residue was purified by flash columnchromatography to yield the title compound as yellow solid (37 mg, 37%yield). MS (ESI): mass calcd. for C₃₁H₃₂N₆O₄S, 584.7; m/z found, 585.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 8.45-8.28 (m, 1H), 8.22-8.05 (m,1H), 7.34-7.18 (m, 1H), 7.11-6.87 (m, 2H), 6.71-6.54 (m, 1H), 6.01-5.85(m, 1H), 4.82-4.57 (m, 1H), 3.98-3.77 (m, 2H), 3.07-2.87 (m, 1H), 2.05(s, 3H), 1.98-1.44 (m, 6H), 1.41-1.21 (m, 6H), 1.26-1.11 (m, 3H),1.09-0.75 (m, 2H).

Example 103:N-(1,6-Dimethylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was made as described in Example 92, and in Step Bthe other isomer was isolated by flash column chromatography to yieldthe title compound as a yellow solid. MS (ESI): mass calcd. forC₂₉H₂₉N₅O₃S, 527.6; m/z found, 528.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.45 (s, 1H), 8.37-8.30 (m, 1H), 7.45-7.37 (m, 2H), 7.33-7.26 (m, 1H),7.21-7.14 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.92 (m, 1H), 6.12-6.05 (m,1H), 4.39-4.28 (m, 1H), 3.48-3.35 (m, 1H), 3.29-3.17 (m, 2H), 2.85-2.75(m, 3H), 2.11 (s, 3H), 2.01-1.86 (m, 4H), 1.43-1.35 (m, 3H).

Example 104:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 159, 100 mg, 0.21 mmol), 3-methylsulfonylpropanoic acid (35 mg,0.23 mmol), HATU (160 mg, 0.42 mmol), and triethylamine (42 mg, 0.42mmol) in DMF (2 mL) was stirred at rt for 2 h, then purified by flashcolumn chromatography to yield the title compound as a white solid (41mg, 32% yield). MS (ESI): mass calcd. for C₃₀H₂₉N₅O₆S₂, 619.7; m/zfound, 620.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.23 (s, 1H),8.43-8.23 (m, 2H), 7.48-7.40 (m, 2H), 7.37 (d, J=8.6 Hz, 1H), 7.23-7.15(m, 1H), 7.14-7.06 (m, 3H), 7.02-6.90 (m, 1H), 5.97 (dd, J=5.4, 2.4 Hz,1H), 4.61-4.35 (m, 1H), 3.87-3.32 (m, 6H), 3.00 (s, 3H), 2.78-2.65 (m,2H), 2.24-2.08 (m, 1H), 2.05 (s, 3H), 2.03-1.87 (m, 1H).

Example 105:(R,E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a mixture of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.30 mmol) and (E)-but-2-enoic acid (52 mg, 0.60mmol) in DMF (2 mL) were added HATU (230 mg, 0.60 mmol), andtriethylamine (60 mg, 0.60 mmol) and was stirred at rt for 4 h. Themixture was purified by flash column chromatography to yield the titlecompound as yellow solid (124 mg, 73.0% yield). MS (ESI): mass calcd.for C₃₁H₂₉N₅O₄S, 567.7; m/z found, 568.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 10.23 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.06 (br, 1H),7.45-7.38 (m, 2H), 7.38-7.33 (m, 1H), 7.20-7.14 (m, 1H), 7.13-7.03 (m,3H), 6.98-6.92 (m, 1H), 6.71-6.58 (m, 1H), 6.52-6.39 (m, 1H), 5.95 (d,J=5.4 Hz, 1H), 4.47-4.12 (m, 1H), 4.06-3.90 (m, 1H), 3.78-3.68 (m, 1H),3.11-2.87 (m, 1H), 2.73-2.55 (m, 1H), 2.03 (s, 3H), 1.93-1.87 (m, 1H),1.83-1.76 (m, 3H), 1.76-1.69 (m, 1H), 1.67-1.55 (m, 1H), 1.43-1.31 (m,1H).

Example 106:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a stirred suspension of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 200 mg, 0.40 mmol) in DMF (3 mL) were added3-[tert-butoxycarbonyl(methyl)amino]propanoic acid (165 mg, 0.812 mmol),HATU (230 mg, 0.61 mmol), and diisopropylethylamine (105 mg, 0.812mmol). The resulting mixture was stirred at rt overnight. The solventwas removed and the residue was partitioned between ethyl acetate andwater. The organic layer was separated, shaken with brine, and driedover anhydrous Na₂SO₄. The residue was purified by flash columnchromatography to yield the intermediate compound as a yellow solid. Theintermediate compound was treated with concentrated HCl (2 mL) in MeOH(15 mL) at rt for about 2 h. After concentrating to dryness, the crudematerial was purified by flash column chromatography to yield the titlecompound as a yellow solid (150 mg, 59% yield). MS (ESI): mass calcd.for C₃₁H₃₂N₆O₄S, 584.7; m/z found, 585.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.43 (s, 1H), 8.37-8.30 (m, 1H), 7.45-7.36 (m, 2H), 7.33-7.26(m, 1H), 7.22-7.14 (m, 1H), 7.13-7.04 (m, 3H), 7.01-6.93 (m, 1H),6.11-6.04 (m, 1H), 4.58-4.32 (m, 1H), 4.12-3.72 (m, 2H), 3.27-2.78 (m,6H), 2.74-2.67 (m, 3H), 2.12 (s, 3H), 2.08-1.99 (m, 1H), 1.93-1.49 (m,3H).

Example 107:(R)-5-(2-Fluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-Fluoro-1-nitro-4-phenoxybenzene

To a mixture of 3-fluoro-4-nitrophenol (2.0 g, 13 mmol), phenylboronicacid (2.3 g, 19 mmol), Cu(OAc)₂ (4.6 g, 25 mmol), and triethylamine (6.4g, 64 mmol) in DCM (60 mL) was added molecular sieves (4A powder<50 μm,2 g). The mixture was stirred at rt under N₂ overnight, filtered,concentrated to dryness, and purified by normal phase flash columnchromatography (SiO₂) to yield the title compound as a yellow solid (2.7g, 91% yield).

Step B:(R)-5-(2-Fluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsB-H in Example 1, and using 2-Fluoro-1-nitro-4-phenoxybenzene in place2-methyl-1-nitro-4-phenoxybenzene in Step B and and tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₆H₂₂FN₅O₃S, 503.5; m/z found, 623.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 9.07 (s, 1H), 8.42-8.34 (m, 1H),8.30 (d, J=7.0 Hz, 1H), 7.65-7.54 (m, 1H), 7.53-7.41 (m, 2H), 7.32-7.22(m, 1H), 7.21-7.12 (m, 3H), 7.02-6.94 (m, 1H), 6.21 (d, J=5.4 Hz, 1H),4.26-4.05 (m, 1H), 3.25-3.08 (m, 2H), 2.93-2.72 (m, 2H), 1.97-1.80 (m,2H), 1.79-1.52 (m, 2H).

Example 108:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27, 150 mg, 0.36 mmol) in DCM (60 mL) was added adrop of DMF, then oxalyl chloride (230 mg, 1.8 mmol) was added. Thereaction was stirred at rt for 3 h, concentrated to dryness, and dilutedin DCM. To this solution was added triethylamine (180 mg, 1.8 mmol) and(3R)-tetrahydrofuran-3-amine (55 mg, 0.63 mmol) and was stirred at rtfor 1 h, concentrated to dryness, and purified by flash columnchromatography to yield the title compound as a yellow solid (61 mg, 34%yield). MS (ESI): mass calcd. for C₂₆H₂₂N₄O₄S, 486.5; m/z found, 487.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.27 (s, 1H), 8.39-8.25 (m, 2H),7.55-7.32 (m, 3H), 7.27-7.17 (m, 1H), 7.17-7.05 (m, 3H), 7.04-6.91 (m,1H), 5.98 (d, J=5.4 Hz, 1H), 4.55-4.37 (m, 1H), 3.96-3.81 (m, 2H),3.75-3.66 (m, 1H), 3.65-3.55 (m, 1H), 2.22-2.12 (m, 1H), 2.07 (s, 3H),1.99-1.87 (m, 1H).

Example 109:N-(1-Acryloylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl 3-aminoazetidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₃N₅O₄S,525.6; m/z found, 526.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ8.29 (d, J=5.5 Hz, 1H), 7.43-7.33 (m, 2H), 7.31-7.23 (m, 1H), 7.17-7.09(m, 1H), 7.08-6.98 (m, 3H), 6.97-6.89 (m, 1H), 6.37-6.23 (m, 1H),6.20-6.08 (m, 1H), 5.98 (d, J=5.5 Hz, 1H), 5.71-5.60 (m, 1H), 4.81-4.69(m, 1H), 4.58-4.47 (m, 1H), 4.24-4.17 (m, 2H), 4.04-3.97 (m, 1H), 2.04(s, 3H).

Example 110:(R)—N-(1-¹³C-Acryloylpiperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: ¹³C-Acrylic acid

To a round bottom flask were added malonic acid (1.7 g, 16 mmol),¹³C-formaldehyde (0.50 g, 16 mmol, 37 wt. % in H₂O), and dry pyridine (7mL) and stirred at reflux for 2 h. Concentrated H₂SO₄ was added dropwiseto neutralize the cooled reaction mixture. The mixture was diluted withH₂O, extracted with Et₂O, dried over anhydrous Na₂SO₄, and concentratedto dryness to yield the title compound as a yellow liquid.

Step B:(R)-5-(4-Methoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 4-methoxy-2-methylaniline in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step C:(R)—N-(1-¹³C-Acryloylpiperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A mixture of(R)-5-(4-methoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(500 mg, 1.1 mmol), ¹³C-acrylic acid (154 mg, 2.11 mmol), EDCI (300 mg,1.6 mmol), HOBt (210 mg, (1.6 mmol), and triethylamine (270 mg, 2.6mmol) in DMF (8 mL) was stirred at rt for 2 h. The reaction mixture wasfirst purified by HPLC, then by flash column chromatography, and finallyby TLC to yield the title compound as a pink solid (8 mg, 1.5%). MS(ESI): mass calcd. for C₂₅H₂₅N₅O₄S, 492.6; m/z found, 493.2 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.33-8.27 (m, 1H), 7.27-7.20 (m, 1H), 7.04-6.98(m, 1H), 6.98-6.91 (m, 1H), 6.86-6.73 (m, 1H), 6.45-5.47 (m, 3H),4.54-3.91 (m, 3H), 3.85 (s, 3H), 3.24-3.09 (m, 1H), 2.97-2.80 (m, 1H),2.13 (s, 3H), 2.12-2.00 (m, 1H), 1.92-1.82 (m, 1H), 1.80-1.67 (m, 1H),1.67-1.51 (m, 1H).

Example 111:N—((R)-1-((R)-2-Amino-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: tert-Butyl((R)-3-methoxy-1-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-1-oxopropan-2-yl)carbamate

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.30 mmol) in DMF (3 mL) were added2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid (99 mg, 0.45mmol), HATU (140 mg, 0.36 mmol), and triethylamine (0.086 mL, 0.62mmol). The reaction mixture was stirred at rt for 4 h. The reactionmixture was purified by flash column chromatography to yield the titlecompound as a yellow solid (186 mg, 88% yield).

Step B:N—((R)-1-((R)-2-Amino-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of tert-butyl((R)-3-methoxy-1-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-1-oxopropan-2-yl)carbamate(186 mg, 0.265 mmol) and HCl/MeOH (2 M in MeOH, 4 mL). The reactionmixture was stirred at rt for 4 h, then the pH was adjusted pH>7 with 2M aqueous NaOH. The mixture was purified by flash column chromatographyto yield the title compound as a yellow solid (71 mg, 44% yield). MS(ESI): mass calcd. for C₃₁H₃₂N₆O₅S, 600.7; m/z found, 601.2 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.30-8.15 (m, 1H), 7.46-7.35 (m, 2H), 7.31-7.21(m, 1H), 7.19-7.12 (m, 1H), 7.12-7.01 (m, 3H), 7.00-6.91 (m, 1H),6.04-5.89 (m, 1H), 4.38-4.26 (m, 1H), 4.18-4.04 (m, 1H), 4.01-3.89 (m,1H), 3.63-3.44 (m, 3H), 3.41-3.33 (m, 2H), 3.18-2.76 (m, 1H), 2.11 (s,3H), 2.02-1.91 (m, 1H), 1.86-1.76 (m, 1H), 1.68-1.54 (m, 1H).

Example 112:(R,E)-N-(1-(2-Cyano-4-methyl-4-morpholinopent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a stirred solution of(R)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 300, 80 mg, 0.16 mmol) in DMF (3 mL) were added 2-cyanoaceticacid (30 mg, 0.35 mmol), HATU (120 mg, 0.54 mmol), anddiisopropylethylamine (45 mg, 0.35 mmol). The resulting mixture wasstirred at rt overnight, concentrated to dryness, and the residue waspartitioned between ethyl acetate and water. The organic layer wasseparated, shaken with brine, and dried over anhydrous Na₂SO₄. Theresidue was purified by flash column chromatography to yield the titlecompound as a yellow solid (68 mg, 75% yield).

Step B:(R,E)-N-(1-(2-Cyano-4-methyl-4-morpholinopent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a sealed reaction tube were added(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(68 mg, 0.12 mmol), 2-methyl-2-morpholinopropanal (28 g, 0.18 mmol),piperidine (15 mg, 0.18 mmol), and EtOH (2 mL). The tube was sealed andheated to 105° C. overnight, cooled to rt, and the residue purified byflash column chromatography to yield the title compound as yellow solid(39 mg, 46% yield). MS (ESI): mass calcd. for C₃₈H₃₉N₇O₅S, 705.8; m/zfound, 706.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.40-8.25 (m, 1H),7.48-7.34 (m, 2H), 7.33-7.23 (m, 1H), 7.25-7.14 (m, 1H), 7.13-7.04 (m,3H), 7.01-6.94 (m, 1H), 6.90-6.80 (m, 1H), 6.13-6.05 (m, 1H), 4.64-3.96(m, 3H), 3.81-3.60 (m, 4H), 3.24-2.83 (m, 2H), 2.69-2.51 (m, 4H), 2.12(s, 3H), 2.05-1.52 (m, 4H), 1.34-1.26 (m, 6H).

Example 113:(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A mixture of(R)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 18) (80 mg, 0.16 mmol), 3-methylsulfonylpropanoic acid (47mg, 0.31 mmol), triethylamine (31 mg, 0.31 mmol), and HATU (118 mg, 0.31mmol) in DMF (2 mL) was stirred at rt for 1 h, then water was added andthe precipitate was collected by filtration. The residue was purified byflash column chromatography to yield the title compound as a white solid(70 mg, 68% yield). MS (ESI): mass calcd. for C₃₁H₃₀FN₅O₆S₂, 651.7; m/zfound, 652.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.39-8.29 (m, 1H),7.44-7.33 (m, 2H), 7.22-7.09 (m, 2H), 7.09-7.04 (m, 3H), 6.16-6.08 (m,1H), 4.44-4.14 (m, 1H), 4.10-3.79 (m, 2H), 3.49-3.38 (m, 2H), 3.24-3.11(m, 1H), 3.06-2.89 (m, 6H), 2.12 (s, 3H), 2.09-2.01 (m, 1H), 1.92-1.78(m, 1H), 1.75-1.52 (m, 2H).

Example 114:(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(2-hydroxyacetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 18) (80 mg, 0.16 mmol), 2-hydroxyacetic acid (24 mg, 0.31mmol), triethylamine (31 mg, 0.31 mmol), and HATU (118 mg, 0.310 mmol)in DMF (2 mL) was stirred at rt for 1 h, then water was added and theprecipitate was collected by filtration. The residue was purified byflash column chromatography to yield the title compound as a white solid(60 mg, 67% yield). MS (ESI): mass calcd. for C₂₉H₂₆FN₅O₅S, 575.6; m/zfound, 576.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.37-8.25 (m, 1H),7.43-7.32 (m, 2H), 7.23-7.17 (m, 1H), 7.16-7.10 (m, 1H), 7.09-7.02 (m,3H), 6.18-6.04 (m, 1H), 4.56-4.17 (m, 3H), 3.97-3.58 (m, 2H), 3.08-2.96(m, 1H), 2.91-2.75 (m, 1H), 2.11 (s, 3H), 2.08-1.97 (m, 1H), 1.88-1.76(m, 1H), 1.73-1.49 (m, 2H).

Example 115:(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(2-methoxyacetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A mixture of(R)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 18) (80 mg, 0.16 mmol), 2-methoxyacetic acid (28 mg, 0.31mmol), triethylamine (31 mg, 0.31 mmol), and HATU (118 mg, 0.310 mmol)in DMF (2 mL) was stirred at rt for 1 h, then water was added and theprecipitate was collected by filtration. The residue was purified byflash column chromatography to yield the title compound as a white solid(60 mg, 66% yield). MS (ESI): mass calcd. for C₃₀H₂₈FN₅O₅S, 589.6; m/zfound, 590.2 [M+H]+. ¹H NMR (400 MHz, CD₃OD): δ 8.40-8.24 (m, 1H),7.44-7.31 (m, 2H), 7.24-7.17 (m, 1H), 7.16-7.10 (m, 1H), 7.09-7.01 (m,3H), 6.16-6.06 (m, 1H), 4.52-4.10 (m, 3H), 3.99-3.69 (m, 2H), 3.38 (s,3H), 3.12-2.96 (m, 1H), 2.87-2.70 (m, 1H), 2.11 (s, 3H), 2.07-1.97 (m,1H), 1.87-1.76 (m, 1H), 1.75-1.47 (m, 2H).

Example 116:(R,Z)—N-(1-(But-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 1,3-Dibromobutan-2-one

To a solution butan-2-one (0.72 g, 10 mmol) in hydrobromic acid (3 mL)in a 3-neck flask equipped with a condenser and a bubble trap filledwith sodium hydroxide was added bromine (3.2 g, 20 mmol) at 0° C. over20 minutes. The mixture was stirred 1 h before the heavier organic phasewas separated. The product was used without further purification (2.30g, 100% yield).

Step B: (Z)-But-2-enoic acid

1,3-Dibromobutan-2-one (2.3 g, 10.0 mmol) was added to a 2 M aqueoussolution of potassium carbonate (100 mL) at 0° C. The mixture wasstirred for 16 h at rt using a condenser. The aqueous solution wasextracted with diethyl ether to remove unreacted material. The aqueousphase was then acidified with 37% hydrochloric acid to a pH of 2 andextracted with diethyl ether. The ether layers were dried over anhydrousMgSO₄ and filtered. The product was used without further purification(166 mg, 19% yield).

Step C:(R,Z)—N-(1-(But-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A mixture of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 300 mg, 0.58 mmol), (Z)-but-2-enoic acid (100 mg, 1.2mmol), HATU (290 mg, 0.76 mmol), and diisopropylethylamine (190 mg, 1.5mmol) in DMF (5 mL) was stirred at rt for 2 h. The mixture was purifiedby HPLC to yield the title compound as white solid (45 mg, 13% yield).MS (ESI): mass calcd. for C₃₁H₂₉N₅O₄S, 567.7; m/z found, 568.3 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ 8.37-8.30 (m, 1H), 7.45-7.36 (m, 2H),7.35-7.26 (m, 1H), 7.21-7.13 (m, 1H), 7.13-7.02 (m, 3H), 7.02-6.93 (m,1H), 6.88-6.38 (m, 1H), 6.15-5.99 (m, 2H), 4.60-3.85 (m, 3H), 3.21-3.04(m, 1H), 2.97-2.80 (m, 1H), 2.38-1.96 (m, 5H), 1.90-1.78 (m, 3H),1.78-1.63 (m, 1H), 1.63-1.50 (m, 1H)

Example 117:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using (R)-1-methylpyrrolidin-3-amine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S,499.6; m/z found, 500.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ8.23 (d, J=5.5 Hz, 1H), 7.42-7.34 (m, 2H), 7.29-7.23 (m, 1H), 7.17-7.10(m, 1H), 7.08-7.04 (m, 2H), 7.03-7.00 (m, 1H), 6.95-6.88 (m, 1H), 5.90(d, J=5.5 Hz, 1H), 4.47-4.37 (m, 1H), 2.86-2.76 (m, 2H), 2.68-2.61 (m,1H), 2.58-2.50 (m, 1H), 2.36 (s, 3H), 2.25-2.15 (m, 1H), 2.03 (s, 3H),1.88-1.80 (m, 1H).

Example 118:(R)—N-(1-Isopropylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 159, 150 mg, 0.31 mmol) in acetone was stirred for 10 min, thenNaBH(OAc)₃ (130 mg, 0.60 mmmol) was added slowly and the mixture wasstirred for 2 h. Next, NaOH (2 mL) was added and the mixture waspurified by flash column chromatography, then preparative TLC to yieldthe title compound as a yellow solid (47 mg, 30% yield). MS (ESI): masscalcd. for C₂₉H₂₉N₅O₃S, 527.6; m/z found, 528.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl3): δ 8.34 (d, J=5.2 Hz, 1H), 7.44-7.34 (m, 2H), 7.20-7.14 (m, 2H),7.13-7.06 (m, 2H), 7.00 (s, 1H), 6.98-6.93 (m, 1H), 6.25-6.11 (m, 1H),6.00 (d, J=5.2 Hz, 1H), 4.68-4.58 (br, 1H), 3.10-3.01 (m, 1H), 2.90-2.80(m, 1H), 2.74-2.64 (m, 1H), 2.49-2.31 (m, 3H), 2.12 (s, 3H), 1.83-1.70(m, 1H), 1.23-1.07 (m, 6H).

Example 119:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-ethyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 4-Ethyl-2-methylaniline

To a mixture of 4-bromo-2-methylaniline (1.86 g, 10.0 mmol), Cs₂CO₃ (9.8g, 30 mmol), and Pd(dppf)Cl₂ (146 mg, 0.200 mmol) in a Schlenk tubeunder a N2 atmosphere was added dry THF (30 mL). To the stirredsuspension was added trialkylborane (30 mL, 1 M solution in THF, 30mmol) in one portion, and the mixture was refluxed for 5 h. The reactionwas cooled to 0° C. and quenched by the addition of 10% aqueous NaOH and30% aqueous H₂O₂. After stirring for 30 min at rt, the mixture wasextracted with EtOAc. The combined organic layers were washedsuccessively with aqueous FeSO₄ and brine, dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness. The residue was purified by flashcolumn chromatography to yield the title compound as a white solid (1.1g, 83% yield).

Step B:5-(4-Ethyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared in a manner analogous to Method 1, stepsC-F in Example 1, and using 4-ethyl-2-methylaniline in place of2-methyl-4-phenoxyaniline in step C.

Step C:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-ethyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of5-(4-ethyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (150 mg, 0.42 mmol), 1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one(Intermediate 5, 119 mg, 0.850 mmol), HATU (320 mg, 0.85 mmol), andtriethylamine (214 mg, 2.12 mmol) in DMF (4 mL) was stirred at rt for 2h. The residue was purified by flash column chromatography to yield thetitle compound as a yellow solid (50 mg, 25% yield). MS (ESI): masscalcd. for C₂₅H₂₅N₅O₃S, 475.6; m/z found, 476.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 10.25 (s, 1H), 8.42-8.22 (m, 2H), 7.35-7.16 (m, 3H),6.71-6.48 (m, 1H), 6.23-6.05 (m, 1H), 5.85 (d, J=5.5 Hz, 1H), 5.73-5.60(m, 1H), 4.60-4.37 (m, 1H), 3.91-3.38 (m, 4H), 2.65 (q, J=7.5 Hz, 2H),2.24-2.07 (m, 1H), 2.05 (s, 3H), 2.03-1.89 (m, 1H), 1.23 (t, J=7.6 Hz,3H).

Example 120:N—((R)-1-((S)-2-Amino-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: tert-Butyl((S)-3-methoxy-1-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-1-oxopropan-2-yl)carbamate

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.30 mmol),(2S)-2-(tert-butoxycarbonylamino)-3-methoxypropanoic acid (99 mg, 0.45mmol), HATU (137 mg, 0.360 mmol), and triethylamine (0.086 mL, 0.62mmol) in DMF (3 mL) was stirred at rt overnight, then purified by flashcolumn chromatography to yield the title compound as a yellow solid (188mg, 89%).

Step B:N—((R)-1-((S)-2-Amino-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of tert-butyl((S)-3-methoxy-1-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-1-oxopropan-2-yl)carbamate(188 mg, 0.268 mmol) in HCl/MeOH (3 mL) was stirred at rt overnight,then the pH was adjusted to pH>7 with 2 M aqueous NaOH, and purified byflash column chromatography to yield the title compound as a yellowsolid (83 mg, 99% yield). MS (ESI): mass calcd. for C₃₁H₃₂N₆O₅S, 600.7;m/z found, 601.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.06 (d, J=5.5, 1H),7.43-7.31 (m, 2H), 7.22-7.05 (m, 4H), 7.04-7.00 (m, 1H), 6.99-6.91 (m,1H), 5.79 (d, J=5.6, 1H), 4.13-3.94 (m, 3H), 3.56-3.51 (m, 1H),3.46-3.39 (m, 1H), 3.39-3.34 (m, 2H), 3.33-3.37 (m, 3H), 3.25-3.20 (m,1H), 2.16-2.01 (m, 4H), 1.96-1.78 (m, 2H), 1.68-1.51 (m, 1H).

Example 121:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridazin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 6-Phenoxypyridazin-3-amine

A solution of 6-chloropyridazin-3-amine (1.3 g, 10 mmol), phenol (3.8 g,40 mmol), and NaOH (1.6 g, 40 mmol) in water (10 mL) was stirred at 190°C. in a sealed tube for 16 h. The mixture was dispersed between EtOAcand water. Another reaction on the same scale was carried out. Theorganic layers were combined, concentrated to dryness, and purified byflash column chromatography to yield the title compound (0.50 g, 27%yield).

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridazin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-G in Example 1, and using 6-phenoxypyridazin-3-amine in place of2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₃N₇O₄S,541.6; m/z found, 542.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.23-8.15 (m,1H), 7.93-7.84 (m, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.51-7.44 (m, 2H),7.33-7.25 (m, 3H), 6.83-6.74 (m, 1H), 6.28-6.14 (m, 2H), 5.75-5.67 (m,1H), 4.22-4.11 (m, 1H), 3.98-3.91 (m, 1H), 3.07-2.93 (m, 1H), 2.15-1.95(m, 2H), 1.94-1.78 (m, 2H), 1.67-1.49 (m, 2H).

Example 122:N—((R)-1-((S)-2-Hydroxy-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.30 mmol), (2S)-2-hydroxy-3-methoxy-propanoicacid (54 mg, 0.45 mmol), HATU (170 mg, 0.45 mmol), and triethylamine(0.084 mL, 0.60 mmol) in DMF (3 mL) was stirred at rt for 4 h, thenpurified by flash column chromatography and preparative TLC to yield thetitle compound as a yellow solid (24 mg, 13%). MS (ESI): mass calcd. forC₃₁H₃₁N₅O₆S, 601.7; m/z found, 602.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.33 (d, J=5.6 Hz, 1H), 7.44-7.36 (m, 2H), 7.35-7.28 (m, 1H), 7.21-7.15(m, 1H), 7.13-7.03 (m, 3H), 7.03-6.95 (m, 1H), 6.07 (d, J=5.6 Hz, 1H),4.69-4.61 (m, 1H), 4.44-4.17 (m, 1H), 4.13-3.89 (m, 2H), 3.71-3.64 (m,1H), 3.61-3.50 (m, 1H), 3.47-3.35 (m, 3H), 3.22-3.10 (m, 1H), 2.01-1.86(m, 1H), 2.12 (s, 3H), 2.07-1.99 (m, 1H), 1.88-1.80 (m, 1H), 1.79-1.49(m, 2H).

Example 123:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using tetrahydropyran-4-amine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₄N₄O₄S,500.6; m/z found, 501.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ8.29-8.25 (m, 1H), 7.39-7.32 (m, 2H), 7.28-7.23 (m, 1H), 7.16-7.09 (m,1H), 7.07-6.99 (m, 3H), 6.94-6.89 (m, 1H), 5.99-5.95 (m, 1H), 4.02-3.97(m, 1H), 3.91-3.83 (m, 2H), 3.42-3.32 (m, 2H), 2.05 (s, 3H), 1.79-1.70(m, 2H), 1.67-1.55 (m, 2H).

Example 124:(R)—N-(1-(2-Hydroxyacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: Benzyl N-[(3R)-1-(2-hydroxyacetyl)-3-piperidyl]carbamate

A mixture of benzyl N-[(3R)-3-piperidyl]carbamate (1.0 g, 3.3 mmol),2-hydroxyacetic acid (225 mg, 3.00 mmol), HATU (1.24 g, 3.26 mmol), andtriethylamine (0.450 mL, 3.26 mmol) in MeCN (10 mL) was stirred at 30°C. for 3 h. The reaction mixture was diluted with EtOAc, washed with 1 Maqueous HCl (3×), saturated aqueous NaHCO₃ (3×) and saturated brine(1×). After filtration and concentration to dryness, the residue waspurified by flash column chromatography to yield the title compound as aclear oil (400 mg, 42%).

Step B: 1-[(3R)-3-Amino-1-piperidyl]-2-hydroxyethanone

A mixture of benzyl N-[(3R)-1-(2-hydroxyacetyl)-3-piperidyl]carbamate(400 mg, 1.4 mmol) and Pd/C (10%, 50 mg) in MeOH (10 mL) was reacted atrt overnight under H₂. The reaction mixture was filtered andconcentrated to dryness to yield the title compound as a clear oil (210mg, 95%), which is used in the next step without further purification.

Step C:(R)—N-(1-(2-Hydroxyacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using1-[(3R)-3-amino-1-piperidyl]-2-hydroxyethanone in place of tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in step G. MS (ESI): mass calcd.for C₂₉H₂₇N₅O₅S, 557.6; m/z found, 558.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 10.20 (s, 1H), 8.32 (d, J=5.4 Hz, 1H), 8.11 (s, 1H),7.46-7.40 (m, 2H), 7.36 (d, J=8.5 Hz, 1H), 7.21-7.17 (m, 1H), 7.12-7.06(m, 3H), 6.99-6.95 (m, 1H), 5.96 (d, J=5.2 Hz, 1H), 4.61-4.28 (m, 1H),4.13-4.05 (m, 3H), 3.81-3.77 (m, 1H), 3.72-3.53 (m, 1H), 2.99-2.64 (m,2H), 2.05 (s, 3H), 1.93-1.89 (m, 1H), 1.75-1.71 (m, 1H), 1.67-1.55 (m,1H), 1.50-1.36 (m, 1H).

Example 125:5-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((S)-1-methylpyrrolidine-3-carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of5-(2-methyl-4-phenoxyphenyl)--oxo-N—((R)-1-((S)-pyrrolidine-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(120 mg, 0.20 mmol) in DCM (2 mL) were added formaldehyde (0.5 mL, 37wt. % in H₂O) and sodium NaBH(OAc)₃ (200 mg, 0.94 mmol) and was reactedat rt overnight. The reaction was quenched with H₂O (10 mL), extractedwith DCM, dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was purified by flash column chromatography toyield the title compound as a yellow solid (54 mg, 44% yield). MS (ESI):mass calcd. for C₃₃H₃₄N₆O₄S, 610.7; m/z found, 611.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.30-8.22 (m, 1H), 7.44-7.34 (m, 2H), 7.30-7.23 (m, 1H),7.19-7.12 (m, 1H), 7.10-7.02 (m, 3H), 7.00-6.93 (m, 1H), 6.04-5.94 (m,1H), 4.35-4.19 (m, 1H), 4.17-3.81 (m, 2H), 3.60-3.46 (m, 1H), 3.27-3.19(m, 1H), 3.16-2.95 (m, 2H), 2.95-2.84 (m, 2H), 2.80-2.70 (m, 1H),2.59-2.44 (m, 3H), 2.15-2.00 (m, 6H), 1.93-1.71 (m, 2H), 1.66-1.50 (m,1H).

Example 126:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using 3-methyl-4-nitrophenol and 2-iodopropane inplace of phenol and 5-fluoro-2-nitrotoluene in step A, and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in step. MS (ESI): mass calcd. forC₂₆H₂₇N₅O₄S, 505.6; m/z found, 506.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.28 (d, J=5.4 Hz, 1H), 7.26-7.18 (m, 1H), 7.00-6.87 (m, 2H), 6.69-6.51(m, 1H), 6.34-6.21 (m, 1H), 6.06-5.97 (m, 1H), 5.79-5.69 (m, 1H),4.74-4.53 (m, 2H), 4.04-3.48 (m, 4H), 2.43-1.98 (m, 5H), 1.42-1.29 (m,6H).

Example 127:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using an analogous method to Example 52Step B using(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98). MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.6; m/z found,514.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30 (d, J=5.6, 1H), 7.43-7.35(m, 2H), 7.31-7.26 (m, 1H), 7.20-7.14 (m, 1H), 7.12-7.08 (m, 2H),7.08-7.03 (m, 1H), 7.01-6.95 (m, 1H), 6.05 (d, J=5.6, 1H), 4.24-4.11 (m,1H), 3.02-2.90 (m, 1H), 2.78-2.68 (m, 1H), 2.36 (s, 3H), 2.29-2.16 (m,2H), 2.12 (s, 3H), 1.95-1.78 (m, 2H), 1.74-1.63 (m, 1H), 1.57-1.45 (m,1H).

Example 128:(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(3-hydroxypropanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 18) (80 mg, 0.16 mmol), 3-hydroxypropanoic acid (28 mg,0.31 mmol), triethylamine (31 mg, 0.31 mmol), and HATU (120 mg, 0.31mmol) in DMF (2 mL) was stirred at rt for 1 h. The reaction was quenchedby the addition of water and the precipitate collected by filtration.The residue was purified by flash column chromatography to yield thetitle compound as a white solid (32 mg, 35% yield). MS (ESI): masscalcd. for C₃₀H₂₈FN₅O₅S, 589.6; m/z found, 590.1 [M+H]+. ¹H NMR (400MHz, CD₃OD): δ 8.43-8.23 (m, 1H), 7.45-7.32 (m, 2H), 7.25-7.17 (m, 1H),7.16-7.10 (m, 1H), 7.09-7.01 (m, 3H), 6.18-6.06 (m, 1H), 4.52-4.07 (m,2H), 3.95-3.76 (m, 3H), 3.18-3.00 (m, 1H), 2.80-2.47 (m, 3H), 2.11 (s,3H), 2.07-1.98 (m, 1H), 1.88-1.76 (m, 1H), 1.74-1.47 (m, 2H).

Example 129:N-(4-Methyl-1,4-oxazepan-6-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:5-(2-Methyl-4-phenoxyphenyl)-N-(1,4-oxazepan-6-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl6-amino-1,4-oxazepane-4-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:N-(4-Methyl-14-oxazepan-6-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of5-(2-methyl-4-phenoxyphenyl)-N-(1,4-oxazepan-6-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(259 mg, 0.502 mmol) in DCM (10 mL) were added formaldehyde (2 mL, 37wt. % in H₂O) and NaBH(OAc)₃ (213 mg, 1.00 mmol) and stirred at rt for 4h. To the reaction mixture were added DCM (50 mL), MeOH (5 mL), water(30 mL), and an aqueous solution of NH₄OH (2 mL). The organic layer wascollected, concentrated to dryness, and purified by flash columnchromatography, then by preparative TLC to yield the title compound as ayellow solid (156 mg, 56.0% yield). MS (ESI): mass calcd. forC₂₈H₂₇N₅O₄S, 529.6; m/z found, 530.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6):δ 8.29 (d, J=5.3 Hz, 1H), 8.14-8.00 (m, 1H), 7.45-7.38 (m, 2H), 7.34 (d,J=8.6 Hz, 1H), 7.20-7.15 (m, 1H), 7.13-7.03 (m, 3H), 6.99-6.92 (m, 1H),5.99-5.89 (d, J=5.4 Hz, 1H), 4.34-4.25 (m, 1H), 3.83-3.77 (m, 1H),2.78-2.53 (m, 4H), 2.33 (s, 3H), 2.03 (s, 3H).

Example 130:(R)—N-(1-(3-(Dimethylamino)propanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 200 mg, 0.4 mmol) in DMF (3 mL) were added3-(dimethylamino)propanoic acid (95 mg, 0.81 mmol), HATU (230 mg, 0.61mmol), and diisopropylethylamine (105 mg, 0.812 mmol) and stirred at rtovernight. The reaction was concentrated to dryness and the residue waspartitioned between EtOAc and water. The organic layer was separated,shaken with brine, dried over anhydrous Na₂SO₄, and purified by flashcolumn chromatography to yield the title compound as a yellow solid (95mg, 40% yield). MS (ESI): mass calcd. for C₃₂H₃₄N₆O₄S, 598.7; m/z found,599.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32-8.21 (m, 1H), 7.46-7.35(m, 2H), 7.32-7.24 (m, 1H), 7.21-7.13 (m, 1H), 7.12-7.03 (m, 3H),7.01-6.92 (m, 1H), 6.07-5.97 (m, 1H), 4.47-4.11 (m, 1H), 4.07-3.69 (m,2H), 3.24-3.03 (m, 3H), 3.02-2.75 (m, 3H), 2.66-2.59 (m, 6H), 2.11 (s,3H), 2.07-1.99 (m, 1H), 1.95-1.53 (m, 3H).

Example 131:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((S)-pyrrolidine-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (S)-tert-Butyl3-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carbonyl)pyrrolidine-1-carboxylate

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 300 mg, 0.6 mmol),(3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (260 mg, 1.2mmol), HATU (456 mg, 1.20 mmol), and triethylamine (120 mg. 1.2 mmol) inDMF (5 mL) was reacted at rt for 2 h, then quenched with H₂O (10 mL),extracted with DCM, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by flash columnchromatography to yield the title compound as a yellow solid (300 mg,72% yield).

Step B:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((S)-pyrrolidine-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (S)-tert-butyl3-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carbonyl)pyrrolidine-1-carboxylate(300 mg, 0.43 mmol) in MeOH (6 mL) was added HCl (37%, 2 mL) and wasreacted at rt for 1 h, then quenched with a saturated solution of NaHCO₃(20 mL), extracted with DCM, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness to yield the title compound as a yellow solid(200 mg, 78% yield). MS (ESI): mass calcd. for C₃₂H₃₂N₆O₄S, 596.7; m/zfound, 597.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.48 (s, 1H), 8.35-8.26(m, 1H), 7.46-7.35 (m, 2H), 7.35-7.28 (m, 1H), 7.19-7.12 (m, 1H),7.08-7.04 (m, 3H), 7.00-6.93 (m, 1H), 6.09-6.02 (m, 1H), 4.53-4.31 (m,1H), 4.21-3.86 (m, 2H), 3.75-3.47 (m, 3H), 3.41-3.34 (m, 2H), 3.26-2.68(m, 2H), 2.46-2.21 (m, 1H), 2.13-2.01 (m, 5H), 1.94-1.54 (m, 3H).

Example 132:N-((3S,4R)-4-Fluoro-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:N-((3S,4R)-4-Fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:N-((3S,4R)-4-Fluoro-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-((3S,4R)-4-fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.2 mmol) and formaldehyde (0.3 mL, 37 wt. % in H₂O) in MeOH (4mL) was added NaBH(OAc)₃ (126 mg, 0.597 mmol) and stirred at rt for 1 h,concentrated to dryness, and purified by flash column chromatography toyield the title compound as a white solid (100 mg, 95% yield). MS (ESI):mass calcd. for C₂₇H₂₄FN₅O₃S, 517.6; m/z found, 518.0 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.32 (d, J=5.5 Hz, 1H), 7.44-7.34 (m, 2H), 7.29 (d,J=8.6 Hz, 1H), 7.20-7.12 (m, 1H), 7.12-7.03 (m, 3H), 6.96 (dd, J=8.6,2.8 Hz, 1H), 6.06 (d, J=5.5 Hz, 1H), 5.26-5.05 (m, 1H), 4.73-4.61 (m,1H), 3.15-3.00 (m, 1H), 2.98-2.81 (m, 3H), 2.44 (s, 3H), 2.11 (s, 3H).

Example 133:(R)-5-(2-Chloro-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-Chloro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 2-chloro-4-fluoro-1-nitrobenzene in place of5-fluoro-2-nitrotoluene in step A, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)-5-(2-Chloro-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-chloro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(104 mg, 0.20 mmol) in DCM (5 mL) were added formaldehyde (0.5 mL, 37wt. % in H₂O) and NaBH(OAc)₃ (85 mg, 0.4 mmol) and stirred at rt for 4h. To the reaction mixture were added DCM (50 mL), MeOH (5 mL), andwater (30 mL). The organic layer was collected, concentrated to dryness,and purified by flash column chromatography to yield the title compoundas yellow solid (15 mg, 14% yield). MS (ESI): mass calcd. forC₂₇H₂₄ClN₅O₃S, 534.0; m/z found, 534.4 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d6): δ 8.85-8.75 (m, 1H), 8.01 (d, J=5.5 Hz, 1H), 7.49-7.43 (m,2H), 7.36-7.32 (m, 1H), 7.26-7.20 (m, 2H), 7.19-7.15 (m, 2H), 7.07-7.02(m, 1H), 5.62 (d, J=5.4 Hz, 1H), 3.95-3.83 (m, 1H), 2.81-2.69 (m, 1H),2.14 (s, 3H), 2.02-1.91 (m, 2H), 1.86-1.76 (m, 2H), 1.71-1.64 (m, 1H),1.56-1.29 (m, 2H).

Example 134:(R,Z)—N-(1-(2-Cyano-4-(dimethylamino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 150 mg, 0.26 mmol), 2-(dimethylamino)-2-methylpropanal (92mg, 0.80 mmol), piperidine (0.3 mL), AcOH (0.1 mL), dioxane (10 mL), and4A molecular sieves (1 g) and was stirred at 100° C. for 1 h under N₂.The mixture was concentrated to dryness and purified by flash columnchromatography to yield the title compound as a yellow solid (103 mg,52.8% yield). MS (ESI): mass calcd. for C₃₆H₃₇N₇O₄S, 663.8; m/z found,664.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.37 (s, 1H), 8.34-8.30 (m,1H), 7.42-7.35 (m, 2H), 7.32-7.25 (m, 1H), 7.20-7.12 (m, 1H), 7.11-7.02(m, 3H), 6.99-6.94 (m, 1H), 6.92-6.76 (m, 1H), 6.09-6.04 (m, 1H),4.44-3.80 (m, 3H), 3.25-2.87 (m, 2H), 2.49-2.31 (m, 6H), 2.13-2.00 (m,4H), 1.96-1.85 (m, 1H), 1.80-1.58 (m, 2H), 1.45-1.30 (m, 6H).

Example 135:(R)-5-(2-Fluoro-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-Fluoro-1-nitro-4-phenoxybenzene

To a solution of 3-fluoro-4-nitrophenol (2.33 g, 19.1 mmol),phenylboronic acid (2.00 g, 12.7 mmol), Cu(OAc)₂ (4.624 g, 25.46 mmol),and triethylamine (6.435 g, 63.65 mmol) in DCM (60 mL) was addedmolecular sieves (4A powder, <50 μm, 2.0 g). The mixture was stirred atroom temperature under N₂ overnight. The reaction was filtered andconcentrated to dryness. The residue was purified by normal phase flashcolumn chromatography (SiO₂) to yield the title compound as a yellowsolid (2.7 g, 91% yield). MS (ESI): mass calcd. for C₁₂H₈FNO₃, 233.20;m/z found, 233.9 [M+H]⁺.

Step B:(R)-5-(2-Fluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsB-H in Example 1, and using 2-fluoro-1-nitro-4-phenoxybenzene, Pd/C, andMeOH in place of -methyl-1-nitro-4-phenoxybenzene, Fe, EtOH/H₂O, andNH₄Cl 2 in step B, and using 2-fluoro-4-phenoxyaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step C:(R)-5-(2-Fluoro-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-fluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.2 mmol) and formaldehyde (1 mL, 37 wt. % in H₂O) in MeOH (10mL) was added NaBH(OAc)₃ (212 mg, 1.00 mmol) and then stirred at roomtemperature for 1 h, concentrated to dryness, and purified by normalphase flash column chromatography (SiO₂) to yield the title compound asa yellow solid (62 mg, 60% yield). MS (ESI): mass calcd. forC₂₇H₂₄FN₅O₃S, 517.6; m/z found, 517.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 8.32 (d, J=7.5 Hz, 1H), 8.23-8.17 (m, 2H), 7.55-7.37 (m, 3H),7.31-7.14 (m, 3H), 7.14-7.06 (m, 1H), 6.98-6.87 (m, 1H), 6.02 (d, J=5.4Hz, 1H), 3.98-3.86 (m, 1H), 2.88-2.77 (m, 1H), 2.72-2.57 (m, 1H), 2.22(s, 3H), 2.05-1.88 (m, 2H), 1.84-1.63 (m, 2H), 1.58-1.43 (m, 1H),1.39-1.25 (m, 1H).

Example 136:(R)-5-(2-Methyl-4-phenoxyphenl)-N-(1-(oxetane-3-carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 100 mg, 0.2 mmol), oxetane-3-carboxylic acid (30 mg, 0.29mmol), triethylamine (40 mg, 0.40 mmol), and HATU (150 mg, 0.40 mmol) inDMF (5 mL) was reacted at rt for 2 h, quenched with H₂O (10 mL),extracted with DCM, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by flash columnchromatography to yield the title compound as an off white solid (48 mg,41% yield). MS (ESI): mass calcd. for C₃₁H₂₉N₅O₅S, 583.7; m/z found,584.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ 8.41-8.34 (m, 1H),7.50-7.41 (m, 2H), 7.38-7.33 (m, 1H), 7.27-7.18 (m, 1H), 7.17-7.09 (m,3H), 7.06-6.97 (m, 1H), 6.12-6.05 (m, 1H), 5.08-4.89 (m, 1H), 4.89-4.75(m, 4H), 4.28-4.18 (m, 1H), 4.04-3.78 (m, 1H), 3.68-3.38 (m, 1H),3.01-2.93 (m, 1H), 2.85-2.75 (m, 1H), 2.20-2.11 (m, 3H), 2.09-2.03 (m,1H), 1.93-1.81 (m, 1H), 1.76-1.64 (m, 1H), 1.63-1.52 (m, 1H).

Example 137:(R)—N-(1-Acryloylpyrrolidin-3-yl)-N-methyl-5-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3R)-3-(methylamino)pyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₄S, 553.6; m/z found, 554.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.84 (s, 1H), 8.37-8.17 (m, 1H),7.48-7.41 (m, 2H), 7.36 (d, J=8.6 Hz, 1H), 7.26-7.15 (m, 1H), 7.14-7.04(m, 3H), 7.03-6.89 (m, 1H), 6.64-6.48 (m, 1H), 6.19-6.04 (m, 1H),6.00-5.89 (m, 1H), 5.75-5.58 (m, 1H), 4.98-4.73 (m, 1H), 3.89-3.34 (m,4H), 3.08-2.95 (m, 3H), 2.29-2.09 (m, 2H), 2.06 (s, 3H).

Example 138:N-((3R,5R)-5-Fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Method 1, Example 1, Steps A-F, 191 mg, 0.458 mmol), tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (100 mg, 0.458 mmol),triethylamine (92 mg, 0.92 mmol), and HATU (348 mg, 0.916 mmol) in DMF(3 mL) was stirred at rt for 3 h. The reaction was quenched by theaddition of water and the precipitate collected by filtration. The solidwas dissolved in MeOH (3 mL) and HCl (3 mL) and the solution was heatedwith stirring at 50° C. for 30 min, concentrated to dryness, and theresidue purified by flash column chromatography to yield the titlecompound as a yellow solid (80 mg, 31% yield). MS (ESI): mass calcd. forC₂₇H₂₄FN₅O₃S, 517.6; m/z found, 518.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.33 (d, J=5.5 Hz, 1H), 7.47-7.36 (m, 2H), 7.34-7.27 (m, 1H), 7.21-7.13(m, 1H), 7.14-7.03 (m, 3H), 7.02-6.94 (m, 1H), 1H),6.07 (d, J=5.5 Hz,1H), 4.76-4.54 (m, 1H), 4.18-4.08 (m, 1H), 3.17-3.01 (m, 2H), 2.79-2.59(m, 2H), 2.36-2.24 (m, 1H), 2.12 (s, 3H), 1.94-1.83 (m, 1H).

Example 139:N-((3S,4S)-4-Hydroxy-1-(3-methoxypropanoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution ofN-((3S,4S)-4-hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 236) (100 mg, 0.2 mmol), 3-methoxypropanoic acid (41 mg, 0.40mmol), triethylamine (40 mg, 0.40 mmol), and HATU (151 mg, 0.398 mmol)in DMF (3 mL) was stirred at rt for 1 h. Water was added and theprecipitate was filtered to give a crude, which was purified by flashcolumn chromatography to yield the title compound as a white solid (65mg, 54% yield). MS (ESI): mass calcd. for C₃₀H₂₉N₅O₆S, 587.6; m/z found,588.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.31 (d, J=5.4 Hz, 1H),7.44-7.35 (m, 2H), 7.33-7.27 (m, 1H), 7.20-7.12 (m, 1H), 7.11-7.02 (m,3H), 7.00-6.93 (m, 1H), 6.06 (d, J=5.5 Hz, 1H), 4.44-4.29 (m, 2H),4.01-3.84 (m, 1H), 3.74-3.57 (m, 4H), 3.52-3.41 (m, 1H), 3.32 (s, 3H),2.65-2.55 (m, 2H), 2.11 (s, 3H).

Example 140:(R)—N-(1-(2-Cyano-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.30 mmol) and 2-cyano-3-methylbut-2-enoic acid(75 mg, 0.60 mmol) in DMF (2 mL) were added HATU (228 mg, 0.600 mmol)and triethylamine (61 mg, 0.60 mmol) and stirred at rt for 4 h. Themixture was purified by flash column chromatography to yield the titleproduct as a yellow solid (105 mg, 58.0% yield). MS (ESI): mass calcd.for C₃₃H₃₀N₆O₄S, 606.7; m/z found, 607.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 10.23 (br, 1H), 8.37-8.25 (m, 1H), 8.21-8.04 (m, 1H),7.47-7.38 (m, 2H), 7.38-7.30 (m, 1H), 7.20-7.14 (m, 1H), 7.14-7.03 (m,3H), 7.00-6.91 (m, 1H), 6.02-5.87 (m, 1H), 4.39-4.09 (m, 1H), 3.82-3.62(m, 2H), 3.16-3.02 (m, 1H), 2.88-2.73 (m, 1H), 2.11-2.01 (m, 6H),1.97-1.92 (m, 1H), 1.92-1.87 (m, 3H), 1.83-1.75 (m, 1H), 1.70-1.59 (m,1H), 1.48-1.38 (m, 1H).

Example 141:(R)—N-(1-Ethylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 159, 150 mg, 0.31 mmol) in MeOH (5 mL) was added acetaldehyde(1 mL) slowly and was stirred for 10 min. Then NaBH(OAc)₃ (127 mg, 0.600mmol) was added slowly and the mixture was stirred for 2 h. NaOH (2 mL)was added and the mixture was purified by flash column chromatography,then preparative TLC to yield the title compound as a yellow solid (58mg, 36% yield). MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.6; m/z found,514.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl3): δ 8.41-8.31 (m, 1H), 7.49-7.34(m, 2H), 7.22-7.15 (m, 2H), 7.15-7.08 (m, 2H), 7.02 (s, 1H), 7.00-6.94(m, 1H), 6.33-6.11 (m, 1H), 6.02 (d, J=3.9 Hz, 1H), 4.76-4.56 (m, 1H),3.13-3.03 (m, 1H), 2.92-2.85 (m, 1H), 2.67-2.55 (m, 3H), 2.47-2.39 (m,1H), 2.35-2.28 (m, 1H), 2.14 (s, 3H), 1.88-1.77 (m, 1H), 1.24-1.13 (m,3H).

Example 142:N—((R)-1-((S)-2,3-Dimethoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (S)-2,3-dimethoxypropanoic acid (Intermediate 19) (50mg, 0.37 mmol) in DCM (5 mL) was added oxalyl dichloride (2 mL) and wasstirred at 60° C. overnight. The reaction was concentrated to drynessand dissolved in DCM (5 mL). This mixture was added to a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 80 mg, 0.16 mmol) and triethylamine (40 mg, 0.40 mmol) inDCM (5 mL) and reacted at room temperature for 30 minutes. The reactionwas quenched with H₂O, extracted with DCM, dried over anhydrous Na₂SO₄,filtered, concentrated to dryness, and purified by normal phase flashcolumn chromatography (SiO₂) to yield the title compound (35 mg, 36%) asan off white solid. MS (ESI): mass calcd. for C₃₂H₃₃N₅O₆S, 615.7; m/zfound, 616.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ 8.43-8.30(m, 1H), 7.50-7.38 (m, 2H), 7.37-7.27 (m, 1H), 7.27-7.17 (m, 1H),7.17-7.07 (m, 3H), 7.04-6.95 (m, 1H), 6.14-6.07 (m, 1H), 4.53-4.36 (m,3H), 4.34-3.84 (m, 3H), 3.72-3.56 (m, 2H), 3.44-3.34 (m, 4H), 3.22-3.03(m, 1H), 3.01-2.77 (m, 1H), 2.19-2.11 (m, 3H), 2.10-2.01 (m, 1H),1.93-1.81 (m, 1H), 1.78-1.49 (m, 2H).

Example 143:N—((R)-1-((R)-2-Hydroxy-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (2R)-Oxirane-2-carboxylic acid, sodium salt

To a solution of methyl (2R)-oxirane-2-carboxylate (170 mg, 1.7 mmol) inMeOH (1 mL) in an ice-salt bath was added a solution of NaOH (73 mg, 1.8mmol) in MeOH (2 mL) dropwise over 10 min. The reaction mixture wasstirred at rt overnight, then ether (5 mL) was added. The mixture wasleft to stand at −10° C. for 1 h, and the precipitate was collected,washed with ether, dried in vacuo to yield the title compound as a whitesolid (170 mg, 92%).

Step B:5-(2-methyl-4-phenoxyphenyl)-N—((R)-1-((R)-oxirane-2-carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 200 mg, 0.40 mmol), (2R)-oxirane-2-carboxylic acid (89 mg,0.80 mmol), HATU (115 mg, 0.600 mmol), and diisopropylethylamine (0.219mL, 1.20 mmol) in DMF (3 mL) was stirred at rt for 15 min, then purifiedby flash column chromatography to yield the title compound as a yellowsolid (160 mg, 70% yield).

Step C:N—((R)-1-((R)-2-Hydroxy-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A mixture of(R)—N-(1-(cyclopropanecarbonyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(150 mg, 0.26 mmol) and NaOMe in MeOH (0.5 M, 9 mL) was stirred at 100°C. in a microwave tube for 5 min, concentrated to dryness, and theresidue purified by flash column chromatography to yield the titlecompound as a yellow solid (40 mg, 25% yield). MS (ESI): mass calcd. forC₃₁H₃₁N₅O₆S, 601.7; m/z found, 602.8 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.33 (d, J=5.6 Hz, 1H), 7.44-7.36 (m, 2H), 7.35-7.26 (m, 1H), 7.20-7.13(m, 1H), 7.11-7.04 (m, 3H), 7.00-6.95 (m, 1H), 6.07 (d, J=5.5 Hz, 1H),4.75-4.60 (m, 1H), 4.48-4.17 (m, 1H), 4.10-3.89 (m, 2H), 3.72-3.52 (m,2H), 3.44-3.33 (m, 3H), 3.23-3.09 (m, 1H), 3.00-2.79 (m, 1H), 2.12 (s,3H), 2.09-2.01 (m, 1H), 1.91-1.80 (m, 1H), 1.79-1.49 (m, 2H).

Example 144:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(2-(trifluoromethyl)acryloyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.28 mmol), 2-(trifluoromethyl)prop-2-enoic acid(78 mg, 0.56 mmol), HATU (138 mg, 0.364 mmol), and diisopropylethylamine(72 mg, 0.56 mmol) in DMF (5 mL) was stirred at rt for 2 h. The mixturewas purified first by HPLC and then by flash column chromatography toyield the title compound as white solid (18 mg, 10% yield). MS (ESI):mass calcd. for C₃₁H₂₆F₃N₅O₄S, 621.6; m/z found, 622.0 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.34-8.27 (m, 1H), 7.42-7.34 (m, 2H), 7.33-7.26 (m,1H), 7.19-7.12 (m, 1H), 7.10-7.01 (m, 3H), 6.98-6.92 (m, 1H), 6.22-6.14(m, 1H), 6.08-6.03 (m, 1H), 5.99-5.87 (m, 1H), 4.57-4.32 (m, 1H),4.12-3.78 (m, 2H), 3.22-3.06 (m, 1H), 2.95-2.80 (m, 1H), 2.11-2.05 (m,4H), 1.97-1.79 (m, 1H), 1.79-1.65 (m, 1H), 1.63-1.53 (m, 1H).

Example 145:5-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((R)-1-methylpyrrolidine-3-carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carbonyl)pyrrolidine-1-carboxylate

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 300 mg, 0.6 mmol),(3R)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (260 mg, 1.2mmol), HATU (456 mg, 1.20 mmol), and triethylamine (121 mg, 1.20 mmol)in DMF (5 mL) was reacted at rt for 2 h. The reaction was quenched withH₂O (10 mL), extracted with DCM, dried over anhydrous Na₂SO₄, filtered,and concentrated to dryness. The residue was purified by flash columnchromatography to yield the title compound as a yellow solid (350 mg,83% yield).

Step B:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((R)-pyrrolidine-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (R)-tert-butyl3-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carbonyl)pyrrolidine-1-carboxylate(350 mg, 0.50 mmol) in MeOH (5 mL) was added HCl (37%, 2 mL) and wasreacted at rt for 1 h. The reaction was quenched by the addition of asaturated solution of NaHCO₃ (20 mL), extracted with DCM, dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness to yield thetitle compound as a yellow solid (200 mg, 67% yield).

Step C:5-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((R)-1-methylpyrrolidine-3-carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((R)-pyrrolidine-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(150 mg, 0.25 mmol) in DCM (2 mL) were added formaldehyde (0.5 mL, 37wt. % in H₂O) and NaBH(OAc)₃ (200 mg, 0.94 mmol) and was stirred at rtovernight. The reaction was quenched with H₂O (10 mL), extracted withDCM, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness.The residue was purified by flash column chromatography to yield thetitle compound as a yellow solid (120 mg, 78% yield). MS (ESI): masscalcd. for C₃₃H₃₄N₆O₄S, 610.7; m/z found, 611.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.43 (s, 1H), 8.35-8.27 (m, 1H), 7.43-7.35 (m, 2H), 7.34-7.27(m, 1H), 7.19-7.12 (m, 1H), 7.10-7.00 (m, 3H), 6.99-6.92 (m, 1H),6.11-6.00 (m, 1H), 4.57-4.32 (m, 1H), 4.26-3.81 (m, 2H), 3.81-3.60 (m,2H), 3.53-3.31 (m, 3H), 3.22-3.00 (m, 1H), 2.96-2.89 (m, 3H), 2.88-2.41(m, 2H), 2.22-1.98 (m, 5H), 1.93-1.47 (m, 3H).

Example 146:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 120 mg, 0.22 mmol), 3-methylsulfonylpropanoic acid (68 mg,0.45 mmol), HATU (110 mg, 0.29 mmol), and diisopropylethylamine (58 mg,0.45 mmol) in DMF (5 mL) was stirred at rt for 2 h. The mixture waspurified by HPLC to yield the title compound as white solid (85 mg, 60%yield). MS (ESI): mass calcd. for C₃₁H₃₁N₅O₆S₂, 633.7; m/z found, 634.0[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34-8.30 (m, 1H), 7.42-7.36 (m, 2H),7.32-7.27 (m, 1H), 7.19-7.13 (m, 1H), 7.10-7.03 (m, 3H), 6.99-6.95 (m,1H), 6.08-6.04 (m, 1H), 4.44-4.13 (m, 1H), 4.08-3.79 (m, 2H), 3.50-3.39(m, 2H), 3.24-3.11 (m, 1H), 3.08-2.83 (m, 6H), 2.12 (s, 3H), 2.08-2.00(m, 1H), 1.91-1.76 (m, 1H), 1.77-1.52 (m, 2H).

Example 147:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: tert-butyl N-[(3R)-1-Methylpyrrolidin-3-yl]carbamate

To a solution of tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (500 mg,2.68 mmol) in MeOH (5 mL) was added formaldehyde (0.4 mL, 37 wt. % inH₂O) and was stirred at rt for 5 min. Next, sodium cyanoborohydride (506mg, 8.05 mmol) was added and was stirred at rt overnight. The reactionmixture was concentrated to dryness and the residue was added to EtOAcand H₂O, and extracted with EtOAc. The combined organic layers werewashed with brine, dried over anhydrous MgSO₄, filtered, andconcentrated to dryness to yield the title compound as a yellow oil (536mg, 100%).

Step B: (3R)-1-Methylpyrrolidin-3-amine

A solution of tert-butyl N-[(3R)-1-methylpyrrolidin-3-yl]carbamate (536mg, 2.84 mmol) in HCl and MeOH (2 M, 2 mL) was stirred at rt for 4 h.The reaction mixture was concentrated to dryness to yield the titlecompound (322 mg, 88%), which was used in next step without furtherpurification.

Step C:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1 (including Chiral resolution Method A after Step F toobtain the *S atropisomer), and using (3R)-1-methylpyrrolidin-3-amine inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S,499.6; m/z found, 500.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.29 (d,J=5.6 Hz, 1H), 7.47-7.35 (m, 2H), 7.31-7.25 (m, 1H), 7.21-7.14 (m, 1H),7.12-7.04 (m, 3H), 7.02-6.94 (m, 1H), 6.03 (d, J=5.6 Hz, 1H), 4.61-4.53(m, 1H), 3.02-2.91 (m, 2H), 2.85-2.78 (m, 1H), 2.69-2.63 (m, 1H), 2.50(s, 3H), 2.43-2.35 (m, 1H), 2.12 (s, 3H), 1.99-1.88 (m, 1H).

Example 148:(R)-5-(2-Methyl-4-(o-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-Methyl-4-(o-tolyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using o-cresol in place of phenol in step A, andusing (R)-tert-butyl 3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G to yield the title compound.

Step B:(R)-5-(2-Methyl-4-(o-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-(o-tolyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(80 mg, 0.16 mmol) in DCM (5 mL), were added formaldehyde (0.5 ml, 37wt. % in H₂O) and NaBH(OAc)₃ (100 mg, 0.47 mmol) and reacted at rt for20 min. The reaction was quenched with H₂O (10 mL), extracted withEtOAc, dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was purified by flash column chromatography toyield the title compound as a yellow solid (26 mg, 31% yield). MS (ESI):mass calcd. for C₂₉H₂₉N₅O₃S, 527.6; m/z found, 528.0 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.38-8.27 (m, 1H), 7.32-7.27 (m, 1H), 7.27-7.19 (m, 2H),7.18-7.07 (m, 1H), 7.03-6.90 (m, 2H), 6.88-6.80 (m, 1H), 6.11-6.02 (m,1H), 4.35-4.15 (m, 1H), 3.45-3.34 (m, 1H), 3.26-3.13 (m, 1H), 2.81-2.65(m, 5H), 2.22 (s, 3H), 2.09 (s, 3H), 2.03-1.96 (m, 2H), 1.86-1.75 (m,1H), 1.66-1.57 (m, 1H).

Example 149:(R)—N-(1-Cyclopropylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 159, 200 mg, 0.41 mmol) in MeOH (5 mL) was added(1-ethoxycyclopropoxy)-trimethylsilane (209 mg, 1.20 mmol) slowly andwas stirred for 10 min, then NaBH₄CN (77 mg, 1.2 mmol) and AcOH (6 mg,0.1 mmol) was added slowly and the mixture was stirred for 2 h. NaOH (2mL) was added and the mixture was purified first by flash columnchromatography, then by preparative TLC to yield the title compound as ayellow solid (65 mg, 29% yield). MS (ESI): mass calcd. for C₂₉H₂₇N₅O₃S,525.6; m/z found, 526.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.50-9.35 (m,1H), 8.33 (d, J=5.4 Hz, 1H), 7.46-7.33 (m, 2H), 7.20-7.13 (m, 2H),7.13-7.05 (m, 2H), 6.99 (s, 1H), 6.97-6.91 (m, 1H), 5.96 (d, J=5.4 Hz,1H), 5.18-4.95 (m, 1H), 3.99-3.60 (m, 2H), 3.37-2.92 (m, 2H), 2.72-2.58(m, 1H), 2.49-2.25 (m, 2H), 2.11 (d, J=2.4, 3H), 1.51-1.28 (m, 2H),1.01-0.75 (m, 2H).

Example 150:(R,E)-N-(1-(2-Cyano-4-methyl-4-(piperidin-1-yl)pent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a sealed tube were added(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 150 mg, 0.265 mmol), 2-methyl-2-(1-piperidyl)propanal (65mg, 0.42 mmol), piperidine (30 mg, 0.35 mmol), and EtOH (3 mL) and thetube was sealed and heated to 105° C. overnight, cooled to rt, and theresidue purified by flash column chromatography to yield the titlecompound as a yellow solid (78 mg, 42% yield). MS (ESI): mass calcd. forC₃₉H₄₁N₇O₄S, 703.9; m/z found, 704.30 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.32 (d, J=5.6 Hz, 1H), 7.46-7.37 (m, 2H), 7.33-7.26 (m, 1H), 7.22-7.15(m, 1H), 7.14-7.05 (m, 3H), 7.02-6.95 (m, 1H), 6.94-6.75 (m, 1H),6.09-6.03 (m, 1H), 4.52-3.71 m, 3H), 3.57-3.34 (m, 1H), 3.24-2.91 (m,1H), 266-2.41 (m, 4H), 2.16-2.10 (m, 3H), 2.09-1.86 (m, 2H), 1.85-1.53(m, 6H), 1.50-1.36 (m, 2H), 1.35-1.24 (m, 6H).

Example 151:(R)—N-(1-(2-Aminoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl(2-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-2-oxoethyl)carbamate

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.30 mmol) in DMF (3 mL) were added2-(tert-butoxycarbonylamino)acetic acid (79 mg, 0.45 mmol), HATU (137mg, 0.360 mmol), and triethylamine (0.167 mL, 1.20 mmol). The reactionmixture was stirred at rt for 4 h and was purified by flash columnchromatography to yield the title compound as a yellow solid (171 mg,86% yield).

Step B:(R)—N-(1-(2-Aminoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl(2-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-2-oxoethyl)carbamate(171 mg, 0.260 mmol) and HCl/MeOH (2 M, 3 mL) was stirred at rt for 4 h,then the pH was adjusted to pH>7 with 2 M aqueous NaOH, and purified byflash column chromatography to yield the title compound as a yellowsolid (95 mg, 65% yield). MS (ESI): mass calcd. for C₂₉H₂₈N₆O₄S, 556.6;m/z found, 557.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.09-8.01 (m, 1H),7.42-7.31 (m, 2H), 7.20-7.05 (m, 4H), 7.04-6.99 (m, 1H), 6.99-6.93 (m,1H), 5.83-5.73 (m, 1H), 4.16-4.02 (m, 1H), 3.99-3.91 (m, 1H), 3.86-3.73(m, 1H), 3.62-3.48 (m, 2H), 3.42-3.30 (m, 1H), 3.27-3.16 (m, 1H), 2.10(s, 3H), 2.07-2.00 (m, 1H), 1.93-1.76 (m, 2H), 1.65-1.51 (m, 1H).

Example 152:(R,E)-N-(1-(2-Cyano-4-(cyclopropylamino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 3-Bromo-3-methylbutanal

To a solution of 3-methylbutanal (500 mg, 5.80 mmol) in Et₂O (3 mL) wasadded slowly a bromine/dioxane complex (720 mg, 2.90 mmol) while coolingwith ice-water. The reaction mixture was stirred at rt for 4 h, and then10% aqueous Na₂S₂O₄ was added. After stirring at rt for 15 min, themixture was extracted with Et₂O/H₂O, the organic layer was collected,washed with brine (10 mL), dried over anhydrous MgSO₄, filtered, andconcentrated to dryness to yield the title compound as a pale yellowliquid (510 mg, 52%).

Step B: 2-(Cyclopropylamino)-2-methylpropanal

To a solution of 3-bromo-3-methylbutanal (450 mg, 2.73 mmol) in Et₂O (10mL) was added cyclopropanamine (545 mg, 9.55 mmol). The reaction mixturewas stirred at rt overnight, then extracted with an Et₂O/water mixture.The organic layer was collected, washed with Et₂O, dried over anhydrousMg₂SO₄, filtered, and concentrated to dryness to yield the titlecompound as a pale yellow liquid (197 mg, 57%).

Step C:(R,E)-N-(1-(2-Cyano-4-(cyclopropylamino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 163 mg, 0.288 mmol) and2-(cyclopropylamino)-2-methylpropanal (110 mg, 0.86 mmol) in iPrOH (5mL) was added piperdine (0.014 mL, 0.14 mmol) and was stirred at 40° C.overnight, concentrated to dryness, and the residue purified by flashcolumn chromatography to yield the title compound as a yellow solid (19mg, 10% yield). MS (ESI): mass calcd. for C₃₇H₃₇N₇O₄S, 675.8; m/z found,676.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.25-8.18 (m, 1H), 7.73-7.64(m, 1H), 7.44-7.35 (m, 2H), 7.26-7.20 (m, 1H), 7.19-7.14 (m, 1H),7.11-7.07 (m, 2H), 7.07-7.03 (m, 1H), 6.99-6.94 (m, 1H), 6.03-5.90 (m,1H), 4.07-3.81 (m, 2H), 3.64-3.43 (m, 1H), 3.06-3.08 (m, 1H), 2.71-2.57(m, 1H), 2.15-2.01 (m, 5H), 1.98-1.88 (m, 1H), 1.76-1.68 (m, 1H),1.65-1.53 (m, 6H), 1.34-1.29 (m, 1H), 1.11-0.89 (m, 4H).

Example 153:5-(2-Methyl-4-phenoxyphenyl)-N-((6S)-6-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using benzyl5-amino-2-methylpiperidine-1-carboxylate (Intermediate 20) in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G and TFA in place of MeOH and aqueous HCl inStep H. Example 153 and Example 173 were separated from the samereaction mixture by flash column chromatography (C-18, MeOH/H₂O)followed by preparative TLC. MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S,513.6; m/z found, 544.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.40-8.32 (m,1H), 7.45-7.37 (m, 2H), 7.33-7.26 (m, 1H), 7.21-7.14 (m, 1H), 7.11-7.02(m, 3H), 7.00-6.92 (m, 1H), 6.12-6.05 (m, 1H), 4.39-4.28 (m, 1H),3.63-3.50 (m, 1H), 3.46-3.37 (m, 1H), 3.37-3.33 (m, 1H), 2.11 (s, 3H),2.06-1.83 (m, 4H), 1.43-1.35 (m, 3H).

Example 154:N-((3S,4R)-4-Fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₆H₂₂FN₅O₃S, 503.5; m/z found, 504.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ 8.37-8.25 (m, 1H),7.42-7.30 (m, 2H), 7.29-7.21 (m, 1H), 7.16-7.09 (m, 1H), 7.08-6.98 (m,3H), 6.95-6.88 (m, 1H), 6.06-5.96 (m, 1H), 5.39-5.18 (m, 1H), 4.83-4.66(m, 1H), 3.67-3.54 (m, 3H), 3.44-3.35 (m, 1H), 2.04 (s, 3H).

Example 155:N-((3R)-1-(3-Methoxybutanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.30 mmol) and 3-methoxybutanoic acid (265 mg,0.900 mmol) in anhydrous DMF (2 mL) were added HATU (342 mg, 0.900 mmol)and diisopropylethylamine (156 mg, 1.20 mmol) and the mixture wasstirred overnight at rt. The reaction mixture was purified by flashcolumn chromatography, then preparative TLC to yield the title compound(41 mg, 23%) as a white solid. MS (ESI): mass calcd. for C₃₂H₃₃N₅O₅S,599.7; m/z found, 600.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.26 (s,1H), 8.35-8.09 (m, 2H), 7.48-7.42 (m, 2H), 7.38-7.31 (m, 1H), 7.23-7.17(m, 1H), 7.16-7.10 (m, 2H), 7.10-7.08 (m, 1H), 7.01-6.95 (m, 1H), 5.93(s, 1H), 4.49-4.11 (m, 1H), 3.99-3.64 (m, 3H), 3.23-3.16 (m, 3H),3.09-2.90 (m, 1H), 2.75-2.54 (m, 2H), 2.38-2.22 (m, 1H), 2.06 (s, 3H),1.99-1.88 (m, 1H), 1.81-1.70 (m, 1H), 1.69-1.54 (m, 1H), 1.52-1.31 (m,1H), 1.14-1.07 (m, 3H).

Example 156:N—((R)-1-((S)-3-Methoxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.28 mmol), (2S)-3-methoxy-2-methylpropanoic acid(43 mg, 0.36 mmol), HATU (137 mg, 0.360 mmol), and triethylamine (0.125mL, 0.897 mmol) in DMF (3 mL) was stirred at rt overnight. The reactionmixture was purified by flash column chromatography to yield the titlecompound as a white solid (120 mg, 70% yield). MS (ESI): mass calcd. forC₃₂H₃₃N₅O₅S, 599.7; m/z found, 600.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.34 (d, J=5.5, 1H), 7.45-7.38 (m, 2H), 7.34-7.27 (m, 1H), 7.23-7.14 (m,1H), 7.12-7.03 (m, 3H), 7.01-6.94 (m, 1H), 6.08 (d, J=5.5, 1H),4.36-4.27 (m, 1H), 4.20-3.87 (m, 2H), 3.65-3.55 (m, 1H), 3.36 (s, 3H),3.27-3.17 (m, 2H), 3.15-2.75 (m, 2H), 2.13 (s, 3H), 2.09-2.00 (m, 1H),1.92-1.70 (m, 2H), 1.63-1.49 (m, 1H), 1.10-0.99 (m, 3H).

Example 157:(R)-5-(4-(2-Ethoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(2-Ethoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 2-ethoxyphenol in place of phenol in step A,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)-5-(4-(2-Ethoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(2-ethoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(542 mg, 0.997 mmol) in DCM (10 mL) were added formaldehyde (1 mL, 37wt. % in H₂O) and NaBH(OAc)₃ (423 mg, 2.00 mmol) and stirred at rt for 4h. To the reaction mixture were added DCM (50 mL), MeOH (5 mL), water(30 mL), and an aqueous solution of NH₄OH (2 mL). The organic layer wasseparated, concentrated to dryness, and purified by flash columnchromatography, then by preparative TLC to yield the title compound as ayellow solid (90 mg, 26% yield). MS (ESI): mass calcd. for C₃₀H₃₁N₅O₄S,557.7; m/z found, 558.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 8.29 (d,J=5.5 Hz, 1H), 8.09-7.97 (m, 1H), 7.26 (d, J=8.7 Hz, 1H), 7.22-7.15 (m,2H), 7.14-7.10 (m, 1H), 7.01-6.96 (m, 1H), 6.94-6.91 (m, 1H), 6.79 (dd,J=8.6, 2.9 Hz, 1H), 5.86 (d, J=5.5 Hz, 1H), 4.04 (q, J=7.0 Hz, 2H),3.99-3.93 (m, 1H), 2.91-2.84 (m, 1H), 2.76-2.68 (m, 1H), 2.26 (s, 3H),2.01 (s, 3H), 2.02-1.92 (m, 2H), 1.82-1.74 (m, 1H), 1.74-1.66 (m, 1H),1.59-1.48 (m, 1H), 1.42-1.32 (m, 1H), 1.19 (t, J=7.0 Hz, 3H).

Example 158:N-((3R)-1-(3-Methoxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 110 mg, 0.22 mmol) in DMF (3 mL) were added3-methoxy-2-methylpropanoic acid (39 mg, 0.33 mmol), HATU (100 mg, 0.26mmol) and triethylamine (0.123 mL, 0.880 mmol) and was stirred at rt for4 h. The reaction mixture was purified by flash column chromatography toyield the title compound as a white solid (70 mg, 52% yield). MS (ESI):mass calcd. for C₃₂H₃₃N₅O₅S, 599.7; m/z found, 600.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.32 (d, J=5.5, 1H), 7.46-7.36 (m, 2H), 7.33-7.28 (m,1H), 7.21-7.15 (m, 1H), 7.11-7.03 (m, 3H), 7.00-6.94 (m, 1H), 6.07 (d,J=5.5, 1H), 4.38-4.23 (m, 1H), 4.20-3.88 (m, 2H), 3.62-3.52 (m, 1H),3.38-3.31 (m, 3H), 3.26-3.19 (m, 2H), 3.15-3.01 (m, 1H), 2.86-2.73 (m,1H), 2.12 (s, 3H), 2.07-2.01 (m, 1H), 1.89-1.79 (m, 1H), 1.76-1.66 (m,1H), 1.61-1.45 (s, 1H), 1.15-1.01 (m, 3H).

Example 159:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₆H₂₃N₅O₃S, 485.6; m/z found, 486.1[M+H]⁺. ¹H NMR (400 MHz, CDCl3): δ 8.31 (d, J=5.5 Hz, 1H), 7.41-7.33 (m,2H), 7.19-7.12 (m, 2H), 7.11-7.05 (m, 2H), 7.01-6.97 (m, 1H), 6.97-6.91(m, 1H), 6.44-6.27 (m, 1H), 5.97 (d, J=5.5 Hz, 1H), 4.64-4.50 (m, 1H),3.25-3.10 (m, 2H), 3.06-2.89 (m, 2H), 2.30-2.17 (m, 1H), 2.11 (s, 3H),1.84-1.72 (m, 1H).

Example 160:N-((3R,5R)-5-Fluoro-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 138, 23 mg, 0.044 mmol) and formaldehyde (0.3 mL, 37 wt. % inH₂O) in MeOH (2 mL) was added NaBH(OAc)₃ (3.2 mg, 0.015 mmol) andstirred at rt overnight, concentrated to dryness, and purified by flashcolumn chromatography to yield the title compound as a white solid (21mg, 86% yield). MS (ESI): mass calcd. for C₂₈H₂₆FN₅O₃S, 531.6; m/zfound, 532.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.27 (d, J=5.5 Hz, 1H),7.39-7.30 (m, 2H), 7.25 (d, J=8.6 Hz, 1H), 7.15-7.07 (m, 1H), 7.06-6.98(m, 3H), 6.91 (dd, J=8.6, 2.8 Hz, 1H), 5.98 (d, J=5.5 Hz, 1H), 4.76-4.56(m, 1H), 4.16-4.08 (m, 1H), 2.79-2.64 (m, 2H), 2.28 (s, 1H), 2.26 (s,3H), 2.19-2.06 (m, 2H), 2.04 (s, 3H), 1.75-1.63 (m, 1H).

Example 161:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propioloylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.28 mmol), prop-2-ynoic acid (42 mg, 0.60 mmol),HATU (148 mg, 0.390 mmol), and diisopropylethylamine (77 mg, 0.60 mmol)in DMF (5 mL) was stirred at rt for 2 h. The reaction mixture waspurified by HPLC to yield the title compound as a yellow solid (82 mg,49% yield). MS (ESI): mass calcd. for C₃₀H₂₅N₅O₄S, 551.6; m/z found,552.6 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ 8.30-8.24 (m, 1H),7.40-7.32 (m, 2H), 7.31-7.25 (m, 1H), 7.15-7.08 (m, 1H), 7.07-6.98 (m,3H), 6.93-6.88 (m, 1H), 5.98-5.93 (m, 1H), 4.39-3.74 (m, 4H), 3.26-3.05(m, 1H), 2.86-2.67 (m, 1H), 2.03 (s, 3H), 1.98-1.89 (m, 1H), 1.84-1.70(m, 1H), 1.69-1.57 (m, 1H), 1.53-1.33 (m, 1H).

Example 162:5-(2-Methyl-4-phenoxyphenyl)-N-(1-methyl-6-oxopiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 5-amino-1-methylpiperidin-2-one in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₅N₅O₄S,527.6; m/z found, 528.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 8.36-8.25(m, 2H), 7.50-7.39 (m, 2H), 7.35 (d, J=8.6 Hz, 1H), 7.25-7.15 (m, 1H),7.14-7.04 (m, 3H), 7.00-6.92 (m, 1H), 5.95 (d, J=5.5 Hz, 1H), 4.31-4.15(m, 1H), 3.50-3.36 (m, 2H), 2.79 (s, 3H), 2.37-2.25 (m, 2H), 2.05 (s,3H), 1.97-1.83 (m, 2H).

Example 163:(R)—N-(1-(3-Aminopropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 3-(tert-Butoxycarbonylamino)propanoic acid

To a solution of 3-aminopropanoic acid (1.0 g, 11 mmol) in DCM (50 mL)at 0° C. under a N₂ atmosphere were added DMAP (137 mg, 1.12 mmol) andtert-butoxycarbonyl tert-butyl carbonate (3.0 g, 14 mmol). The reactionwas warmed to rt overnight. The reaction mixture was concentrated todryness and was used in the next step without purification (1.5 g, 70%yield).

Step B: (R)-tert-Butyl(3-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-3-oxopropyl)carbamate

To a stirred solution of(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.30 mmol) in DMF (3 mL) were added3-(tert-butoxycarbonylamino)propanoic acid (170 mg, 0.90 mmol), HATU(230 mg, 0.60 mmol), and diisopropylethylamine (120 mg, 0.93 mmol) andstirred at rt overnight. The solvent was removed and the residue waspartitioned between ethyl acetate and water. The organic layer wasseparated, shaken with brine, and dried over anhydrous Na₂SO₄. Theresidue was purified by flash column chromatography to yield the titlecompound as brown solid (50 mg, 25% yield).

Step C:(R)—N-(1-(3-Aminopropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (R)-tert-Butyl(3-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-3-oxopropyl)carbamate(50 mg, 0.075 mmol) in MeOH (15 mL) was added concentrated HCl (1 mL)and was stirred at rt for about 2 h. The reaction was concentrated todryness and purified by flash column chromatography to yield the titlecompound as a yellow solid (26 mg, 57% yield). MS (ESI): mass calcd. forC₃₀H₃₀N₆O₄S, 570.7; m/z found, 571.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.49 (s, 1H), 8.29-8.21 (m, 1H), 7.44-7.33 (m, 2H), 7.28-7.22 (m, 1H),7.18-7.10 (m, 1H), 7.10-7.01 (m, 3H), 6.99-6.91 (m, 1H), 6.04-5.94 (m,1H), 4.29-4.06 (m, 1H), 4.05-3.60 (m, 2H), 3.20-3.09 (m, 3H), 3.00-2.74(m, 2H), 2.13-2.06 (m, 3H), 2.05-1.52 (m, 5H).

Example 164:N-((3R,5S)-5-Fluoro-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-((3R,5S)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 167, 90 mg, 0.16 mmol) and formaldehyde (0.5 mL, 37 wt. % inH₂O) in methanol (25 mL) was added NaBH(OAc)₃ (102 mg, 0.481 mmol) andwas stirred at rt for 16 h, concentrated to dryness, and purified byflash column chromatography to yield the title compound as a white solid(78 mg, 84% yield). MS (ESI): mass calcd. for C₂₈H₂₆FN₅O₃S, 531.6; m/zfound, 532.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.29 (d, J=5.5 Hz,1H), 8.15 (s, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.48-7.39 (m, 2H), 7.37-7.30(m, 1H), 7.23-7.15 (m, 1H), 7.14-7.05 (m, 3H), 7.00-6.95 (m, 1H), 5.93(d, J=5.4 Hz, 1H), 4.91 (d, J=47.4 Hz, 1H), 4.27-4.15 (m, 1H), 2.91-2.80(m, 2H), 2.19 (s, 3H), 2.15-1.88 (m, 6H), 1.78-1.50 (m, 1H).

Example 165:N-(1,3-Dimethylpiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of5-(2-methyl-4-phenoxyphenyl)-N-(3-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 172, 90 mg, 0.18 mmol) and formaldehyde (0.5 mL, 37 wt. % inH₂O) in methanol (15 mL) was added NaBH(OAc)₃ (111 mg, 0.524 mmol) andwas stirred at rt for 3 h, concentrated to dryness, and purified byflash column chromatography to yield the title compound as a yellowsolid (71 mg, 77% yield). MS (ESI): mass calcd. for C₂₉H₂₉N₅O₃S, 527.6;m/z found, 528.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.37-8.20 (m, 1H),7.45-7.34 (m, 2H), 7.34-7.20 (m, 1H), 7.20-7.11 (m, 1H), 7.11-7.02 (m,3H), 6.99-6.93 (m, 1H), 6.10-5.94 (m, 1H), 4.35-4.15 (m, 0.5H),3.74-3.55 (m, 0.5H), 3.10-2.68 (m, 3H), 2.65-2.37 (m, 3H), 2.35-2.20 (m,1H), 2.12 (s, 3H), 2.05-1.70 (m, 3H), 1.08-0.91 (m, 3H).

Example 166:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(2-oxopiperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 4-aminopiperidin-2-one in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₃N₅O₄S,513.6; m/z found, 514.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 8.46-8.30(br, 1H), 8.30-8.20 (m, 1H), 7.60-7.54 (m, 1H), 7.45-7.39 (m, 2H),7.34-7.26 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.07 (m, 2H), 7.07-7.03 (m,1H), 6.97-6.92 (m, 1H), 5.93-5.83 (m, 1H), 4.20-4.13 (m, 1H), 3.22-3.13(m, 2H), 2.45-2.41 (m, 1H), 2.31-2.23 (m, 1H), 2.03 (s, 3H), 1.96-1.91(m, 1H), 1.77-1.68 (m, 1H).

Example 167:N-((3R,5S)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(3R,5S)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 3) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₄FN₅O₃S,517.6; m/z found, 518.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 8.29 (d,J=5.5 Hz, 1H), 8.15 (s, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.52-7.38 (m, 2H),7.34 (d, J=8.6 Hz, 1H), 7.24-7.15 (m, 1H), 7.15-7.03 (m, 3H), 7.02-6.91(m, 1H), 5.93 (d, J=5.5 Hz, 1H), 4.90 (s, 0.5H), 4.78 (s, 0.5H),4.20-4.09 (m, 1H), 3.05-2.90 (m, 2H), 2.79-2.51 (m, 2H), 2.20-2.07 (m,1H), 2.04 (s, 3H), 1.98-1.72 (m, 1H).

Example 168:N-((3R,5R)-5-Hydroxy-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution ofN-((3R,5R)-5-hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 179, 80 mg, 0.16 mmol) in DCM (5 mL) was treated withformaldehyde (0.5 mL, 37 wt. % in H₂O). To the stirred reaction mixturewas added NaBH(OAc)₃ (100 mg, 0.47 mmol) and the reaction mixture wasmaintained at rt for 1 h, and then concentrated to dryness. The residuewas purified by flash column chromatography to yield the title compoundas a yellow solid (53 mg, 59% yield). MS (ESI): mass calcd. forC₂₈H₂₇N₅O₄S, 529.6; m/z found, 530.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.44 (s, 1H), 8.36-8.30 (m, 1H), 7.46-7.37 (m, 2H), 7.34-7.27 (m, 1H),7.21-7.14 (m, 1H), 7.13-7.04 (m, 3H), 7.01-6.94 (m, 1H), 6.11-6.04 (m,1H), 4.76-4.61 (m, 1H), 4.28-4.21 (m, 1H), 3.48-3.36 (m, 1H), 3.24-3.10(m, 1H), 3.08-2.95 (m, 1H), 2.84-2.75 (m, 4H), 2.12 (s, 3H), 2.09-1.99(m, 1H), 1.96-1.82 (m, 1H).

Example 169:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1 (including Chiral resolution Method A after Step F toobtain the *R atropisomer), and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₉H₂₅N₅O₄S, 539.6; m/z found, 540.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.23 (s, 1H), 8.42-8.25 (m, 2H),7.52-7.31 (m, 3H), 7.24-7.05 (m, 4H), 7.02-6.90 (m, 1H), 6.68-6.48 (m,1H), 6.13 (d, J=18.0 Hz, 1H), 6.03-5.93 (m, 1H), 5.72-5.57 (m, 1H),4.60-4.32 (m, 1H), 3.91-3.35 (m, 4H), 2.24-1.91 (m, 5H).

Example 170:(R)-5-(4-(2-Ethylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(2-Ethylphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 2-ethylphenol in place of phenol in step A,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)-5-(4-(2-Ethylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(2-ethylphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(60 mg, 0.11 mmol) in DCM (2 mL) were added formaldehyde (0.5 mL, 37 wt.% in H₂O) and NaBH(OAc)₃ (70 mg, 0.33 mmol) and was reacted at rt for 20min. The reaction was quenched by the addition of H₂O (10 mL), extractedwith DCM, dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was purified by flash column chromatography andpreparative TLC to yield the title compound as a yellow solid (51 mg,82% yield). MS (ESI): mass calcd. for C₃₀H₃₁N₅O₃S, 541.7; m/z found,544.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.28 (d, J=5.6 Hz, 1H),7.35-7.29 (m, 1H), 7.27-7.20 (m, 2H), 7.18-7.12 (m, 1H), 7.00-6.93 (m,2H), 6.88-6.83 (m, 1H), 6.02 (d, J=5.6 Hz, 1H), 4.21-4.06 (m, 1H),2.96-2.87 (m, 1H), 2.76-2.68 (m, 1H), 2.66-2.56 (m, 2H), 2.33 (s, 3H),2.26-2.13 (m, 2H), 2.09 (s, 3H), 1.91-1.78 (m, 2H), 1.72-1.63 (m, 1H),1.55-1.48 (m, 1H), 1.22-1.16 (m, 3H).

Example 171:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(quinuclidin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 3-aminoquinuclidine and THF in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and DMF instep G. MS (ESI): mass calcd. for C₂₉H₂₇N₅O₃S, 525.6; m/z found, 526.0[M+H]⁺. 1H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.42-8.08 (m, 1H),7.59-7.40 (m, 2H), 7.40-7.07 (m, 6H), 7.07-6.90 (m, 1H), 6.05-5.70 (m,1H), 4.08 (s, 1H), 3.10-2.69 (m, 5H), 2.14-1.93 (m, 6H), 1.86-1.67 (m,2H), 1.67-1.47 (m, 1H).

Example 172:5-(2-Methyl-4-phenoxyphenyl)-N-(3-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl4-amino-3-methylpiperidine-1-carboxylate and THF in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and DMF in step G. MS(ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.6; m/z found, 514.3 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD and DMSO-d₆): δ 8.34-8.24 (m, 1H), 7.44-7.33 (m,2H), 7.28 (d, J=8.5 Hz, 1H), 7.18-7.09 (m, 1H), 7.10-6.99 (m, 3H),6.97-6.86 (m, 1H), 5.99-5.90 (m, 1H), 4.38-4.15 (m, 0.5H), 3.86-3.78 (m,0.5H), 3.35-3.14 (m, 2H), 3.12-2.92 (m, 2H), 2.77-2.62 (m, 0.5H),2.33-2.18 (m, 0.5H), 2.03 (s, 3H), 1.97-1.77 (m, 2H), 0.98-0.85 (m, 3H).

Example 173:5-(2-Methyl-4-phenoxyphenyl)-N-((6R)-6-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using benzyl5-amino-2-methylpiperidine-1-carboxylate (Intermediate 20) in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G and TFA in place of MeOH and aqueous HCl inStep H. Example 153 and Example 173 were separated from the samereaction mixture by flash column chromatography (C-18, MeOH/H₂O)followed by preparative TLC. MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S,513.6; m/z found, 544.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.40-8.33 (m,1H), 7.45-7.37 (m, 2H), 7.33-7.26 (m, 1H), 7.21-7.14 (m, 1H), 7.11-7.02(m, 3H), 7.00-6.92 (m, 1H), 6.12-6.05 (m, 1H), 4.33-4.17 (m, 1H),3.60-3.48 (m, 1H), 3.23-3.15 (m, 1H), 2.97-2.84 (m, 1H), 2.15-2.04 (m,5H), 1.84-1.73 (m, 1H), 1.67-1.58 (m, 1H), 1.41-1.32 (m, 3H).

Example 174:(R)—N-(5,5-Difluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(5R)-5-amino-3,3-difluoropiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₃F₂N₅O₃S, 535.6; m/z found, 535.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 8.32 (d, J=5.5 Hz, 1H), 8.07 (d,J=8.0 Hz, 1H), 7.47-7.41 (m, 2H), 7.36 (d, J=8.6 Hz, 1H), 7.22-7.18 (m,1H), 7.16-7.05 (m, 3H), 7.01-6.95 (m, 1H), 5.96 (d, J=5.5 Hz, 1H),4.10-4.00 (m, 1H), 3.03-2.90 (m, 2H), 2.80-2.66 (m, 1H), 2.45-2.40 (m,1H), 2.37-2.27 (m, 1H), 2.05 (s, 3H), 2.02-1.94 (m, 1H).

Example 175:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2,6-difluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 1,3-Difluoro-2-nitro-5-phenoxybenzene

To a solution of 3,5-difluoro-4-nitrophenol (Intermediate 26) (493 mg,2.82 mmol) in CH₃CN (45 mL) was added (2-trimethylsilylphenyl)trifluoromethanesulfonate (1.0 mL, 4.2 mmol), followed by cesiumfluoride (1.28 g, 8.45 mmol). The mixture was stirred at rt overnight(argon needle inlet). The reaction mixture was washed with saturatedaqueous NaCl (50 mL) and the aqueous phase was extracted once with Et₂O(50 mL). The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, concentrated to dryness, and purified by flash columnchromatography to yield the title compound as a yellow oil mass (450.7mg. 64%)

Step B: 2,6-difluoro-4-phenoxyaniline

The title compound was prepared in a manner analogous to Method 1, stepB in Example 1, and using 1,3-difluoro-2-nitro-5-phenoxybenzene in placeof 2-Methyl-1-nitro-4-phenoxybenzene in step B.

Step C:2-Chloro-4-(2,6-difluoro-4-phenoxyanilino)pyridine-3-carbonitrile

The title compound was prepared in a manner analogous to Method 1, stepC in Example 1, and using 2,6-difluoro-4-phenoxyaniline in place of2-Methyl-4-phenoxyaniline in step C.

Step D: tert-Butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate

A 20 mL microwave vial was charged with (R)-1-boc-3-aminopiperdine (5.0g, 25 mmol). The vial was sealed, evacuated, and back-filled with argonthree times. Methyl 2-mercaptoacetate (6.7 mL, 170 mmol) was added viasyringe in one portion and was heated to 150° C. in an oil bath. After 1h 35 minutes, the mixture was cooled to rt and purified by flash columnchromatography to yield a colorless oil (6.15 g. 90%).

Step E: (R)-tert-Butyl3-(3-amino-4-((2,6-difluoro-4-phenoxyphenyl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate

To the sealed tube containing2-chloro-4-(2,6-difluoro-4-phenoxyanilino)pyridine-3-carbonitrile (580mg, 1.6 mmol) was added a 0.56 M solution of tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate in dioxane (3.5mL, 1.9 mmol). The resulting brown suspension was heated in the sealedtube under argon at 150° C. in an oil bath for 15 minutes. The mixturewas cooled to rt and was used directly in the next reaction.

Step F: (R)-tert-butyl3-(5-(2,6-difluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a solution of (R)-tert-butyl3-(3-amino-4-((2,6-difluoro-4-phenoxyphenyl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate(966 mg, 1.62 mmol) in dioxane (3.5 mL) was added CDI (1.05 g, 6.49mmol) and was heated at 150° C. in an oil bath for 10 minutes. Themixture was cooled to rt and was partitioned between EtOAc (50 mL) andwater (50 mL). The aqueous phase was extracted with EtOAc (2×50 mL) andthe combined organic extracts were washed with saturated aqueous NaCl(50 mL). The organic phase was dried over anhydrous Na₂SO₄ and filtered.The filtrate was concentrated to dryness and the residue was purified byflash column chromatography to yield the title compound as a tan solid(562 mg, 56%).

Step G:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2,6-difluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A suspension of(R)-5-(2,6-difluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 235) (28.6 mg, 0.0548 mmol) in THF (2 mL) was sonicated toproduce a milky suspension. To this suspension was added triethylamine(11 μL, 0.082 mmol) followed by a solution of(E)-2-cyano-3-cyclopropylprop-2-enoyl chloride (Intermediate 23) (0.060mmol) in CHCl₃ (from step H above). The reaction mixture was stirred atrt for 1 h, concentrated to dryness, and purified by flash columnchromatography and HPLC to yield the title compound as a white solid(17.9 mg, 51%). MS (ESI): mass calcd. for C₃₃H₂₆F₂N₆O₄S, 640.7; m/zfound, 641.3 [M+H]⁺. 1H NMR (400 MHz, CDCl₃) δ 9.42-9.68 (m, 1H), 8.45(d, J=5.56 Hz, 1H), 7.39-7.55 (m, 2H), 7.29 (t, J=7.33 Hz, 1H), 7.14 (d,J=7.58 Hz, 2H), 6.70 (d, J=9.09 Hz, 2H), 6.28 (d, J=6.06 Hz, 1H),4.13-4.22 (m, 1H), 3.39-4.02 (m, 3H), 1.65-2.16 (m, 6H), 1.21-1.33 (m,3H), 0.92-1.04 (m, 1H).

Example 176:¹³C—(R,Z)—N-(1-(2-Cyano-3-cycloproplacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: ¹³C-Cyclopropanecarbaldehyde

A solution of ¹³C-N,N-dimethylformamide (500 mg, 6.75 mmol) in THF (10mL) was slowly added to cyclopropylmagnesiumbromide in THF (0.5 M, 15mL, 7.4 mmol) in an ice bath under N₂ over a period of 5 min. Themixture was brought to rt and stirred for 1 h, then the mixture wasacidified with 3 M aqueous HCl, extracted with Et₂O, dried overanhydrous Na₂SO₄, and concentrated to dryness to yield the titlecompound as a pale yellow oil (320 mg, 62%), which was used withoutpurification in next step.

Step B:¹³C—(R,Z)—N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(4-methoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(prepared as in Example 110, Step B, 250 mg, 0.57 mmol), 2-cyanoaceticacid (97 mg, 1.1 mmol), triethylamine (115 mg, 1.14 mmol), and HATU (434mg, 1.14 mmol) in DMF (3 mL) was stirred at rt for 3 h. The reaction wasquenched by the addition of water and the precipitate was filtered togive a pale yellow solid. To a mixture of this solid and¹³C-cyclopropanecarbaldehyde (122 mg, 1.71 mmol) in EtOH (5 mL) wasadded piperidine (97 mg, 1.1 mmol) and was stirred at rt for 1 h,concentrated to dryness, and purified by by flash chromatography (C-18,MeOH/H₂O) to yield the title compound as a white solid (12 mg, 4%). MS(ESI): mass calcd. for C₂₉H₂₈N₆O₄S, 557.6; m/z found, 558.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆ and CD₃OD): δ 8.25 (d, J=5.3 Hz, 1H), 7.19 (d,J=8.8 Hz, 1H), 6.97 (s, 1H), 6.89 (d, J=8.8 Hz, 1H), 6.53-6.01 (m, 1H),5.86 (d, J=5.3 Hz, 1H), 4.39-4.21 (m, 1H), 3.90-3.84 (m, 1H), 3.78 (s,3H), 3.72-3.63 (m, 1H), 3.30-3.13 (m, 1H), 2.95-2.84 (m, 1H), 2.03 (s,3H), 2.00-1.89 (m, 2H), 1.86-1.78 (m, 1H), 1.68-1.63 (m, 1H), 1.52-1.44(m, 1H), 1.09-0.97 (m, 2H), 0.82-0.75 (m, 2H).

Example 177:¹³C—(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was made using the same procedure as described inExample 176, but the other isomer was isolated by flash chromatography(C-18, MeOH/H₂O). MS (ESI): mass calcd. for C₂₉H₂₈N₆O₄S, 557.6; m/zfound, 558.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ 8.26 (d,J=5.4 Hz, 1H), 7.20 (d, J=8.7 Hz, 1H), 6.97 (s, 1H), 6.90 (d, J=8.6 Hz,1H), 6.77-6.24 (m, 1H), 5.88 (d, J=5.4 Hz, 1H), 3.95-3.82 (m, 2H), 3.78(s, 3H), 3.71-3.57 (m, 1H), 3.10-2.76 (m, 2H), 2.03 (s, 3H), 1.97-1.86(m, 2H), 1.82-1.75 (m, 1H), 1.71-1.61 (m, 1H), 1.503-1.43 (m, 1H),1.16-1.09 (m, 2H), 1.00-0.88 (m, 1H), 0.84-0.77 (m, 1H).

Example 178:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(cyclohexyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:2-Chloro-4-[4-(cyclohexoxy)-2-methylanilino]pyridine-3-carbonitrile

To a cold (0° C.) solution of2-chloro-4-(4-hydroxy-2-methylanilino)pyridine-3-carbonitrile(Intermediate 14) (1.0 g, 3.8 mmol), cyclohexanol (1.16 g, 11.6 mmol),and PPh₃ (1.5 g, 5.7 mmol) in THF (20 mL) was added DIAD (1.17 g, 5.79mmol) and was stirred at rt overnight. The mixture was concentrated todryness and the residue was purified by flash column chromatography toyield the title compound as a yellow solid (400 mg, 30% yield).

Step B:(R)-5-(4-(Cyclohexyloxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsD-H in Example 1, and using2-chloro-4-[4-(cyclohexoxy)-2-methylanilino]pyridine-3-carbonitrile inplace of 2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrilein step D, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step C:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(cyclohexyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a stirred solution of(R)-5-(4-(cyclohexyloxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.20 mmol) in DMF (3 mL) were added(E)-2-cyano-3-cyclopropylprop-2-enoic acid (Intermediate 17) (43 mg,0.31 mmol), HATU (120 mg, 0.32 mmol), and diisopropylethylamine (67 mg,0.52 mmol) and was stirred at rt overnight, concentrated to dryness, andthe residue partitioned between ethyl acetate and water. The organiclayer was separated, shaken with brine, and dried over anhydrous Na₂SO₄.The residue was purified by flash column chromatography to yield thetitle compound as a brown solid (26 mg, 16% yield). MS (ESI): masscalcd. for C₃₄H₃₆N₆O₄S, 624.8; m/z found, 625.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.46 (s, 1H), 8.31 (d, J=5.5 Hz, 1H), 7.22-7.14 (m, 1H),7.01-6.95 (m, 1H), 6.95-6.88 (m, 1H), 6.60-6.48 (m, 1H), 6.03 (d, J=5.5Hz, 1H), 4.44-4.33 (m, 1H), 4.11-3.94 (m, 2H), 2.10 (s, 3H), 2.06-1.95(m, 4H), 1.94-1.65 (m, 5H), 1.64-1.26 (m, 10H), 1.25-1.14 (m, 2H),1.06-0.77 (m, 2H).

Example 179:N-((3R,5R)-5-Hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(3R,5R)-3-amino-5-hydroxypiperidine-1-carboxylate (Intermediate 4) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₄S,515.6; m/z found, 516.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.24 (d,J=5.6 Hz, 1H), 7.45-7.35 (m, 2H), 7.29-7.23 (m, 1H), 7.20-7.13 (m, 1H),7.12-7.04 (m, 3H), 7.00-6.94 (m, 1H), 5.98 (d, J=5.6 Hz, 1H), 4.52-4.37(m, 1H), 4.09-3.98 (m, 1H), 3.22-3.11 (m, 1H), 2.91-2.81 (m, 2H),2.76-2.65 (m, 1H), 2.12 (s, 3H), 2.07-1.87 (m, 2H).

Example 180:(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1 (including Chiral resolution Method A after Step F toobtain the *R atropisomer), and using (3R)-1-methylpiperidin-3-amine inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S,513.6; m/z found, 514.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.31 (d,J=5.5, 1H), 7.46-7.36 (m, 2H), 7.33-7.24 (m, 1H), 7.22-7.14 (m, 1H),7.12-7.02 (m, 3H), 7.02-6.93 (m, 1H), 6.05 (d, J=5.6, 1H), 4.24-4.11 (m,1H), 3.02-2.89 (m, 1H), 2.80-2.66 (m, 1H), 2.36 (s, 3H), 2.31-2.17 (m,2H), 2.12 (s, 3H), 1.94-1.80 (m, 2H), 1.75-1.61 (m, 1H), 1.56-1.45 (m,1H).

Example 181:(R)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To an oven dried microwave vial with a stir bar under Ar were added(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860, 313.4 mg, 0.523 mmol), cyanoacetic acid (72 mg, 0.84mmol), HATU (258 mg, 0.680 mmol), and triethylamine (0.147 mL, 1.04mmol) in THF (2.1 mL) and was warmed in the microwave for 5 min at 100°C. The reaction mixture was filtered and purified by HPLC to yield thetitle compound (203 mg, 58% yield). MS (ESI): mass calcd. forC₂₉H₂₄N₆O₄S, 552.6; m/z found, 553.0 [M+H]+. ¹H NMR (500 MHz, CD₃OD): δ8.42-8.24 (m, 1H), 7.50-7.37 (m, 4H), 7.24-7.05 (m, 5H), 6.27-6.13 (m,1H), 4.53-4.30 (m, 1H), 4.03-3.60 (m, 4H), 3.23-2.68 (m, 2H), 2.16-1.48(m, 4H).

Example 182:(R)—N-(1-Methylpiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To an oven dried microwave vial with a stir bar under Ar were added(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860, 69.5 mg, 0.143 mmol), sodium cyanoborohydride (19.7 mg,0.313 mmol), and MeOH (3 mL) and was cooled to 0° C. in an ice bath.Next, was added via a syringe was aqueous formaldehyde (0.01 mL, 37 wt.% in H₂O) and allowed to slowly warm to rt. The reaction mixture wasfiltered and purified by HPLC to yield the title compound as a whitefluffy solid (25.3 mg, 35% yield). MS (ESI): mass calcd. forC₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.27 (d, J=5.6 Hz, 1H), 7.50-7.31 (m, 4H), 7.24-7.03 (m, 6H), 6.14 (d,J=5.6 Hz, 1H), 4.27-4.05 (m, 1H), 2.99-2.63 (m, 2H), 2.33 (s, 3H),2.25-2.07 (m, 2H), 1.97-1.41 (m, 4H).

Example 183:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butylmethyl(2-(3-(5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-2-oxoethyl)carbamate

To a solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98, 30 mg, 0.056 mmol),2-[tert-butoxycarbonyl(methyl)amino]acetic acid (Intermediate 21) (16mg, 0.085 mmol), HATU (28 mg, 0.074 mmol), and triethylamine (0.031 mL,0.22 mmol) were added to DMF (1.5 mL). The reaction mixture was stirredat rt overnight, then purified by flash column chromatography andpreparative TLC to yield the title compound as a yellow solid.

Step B:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butylmethyl(2-(3-(5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-2-oxoethyl)carbamate(25 mg, 0.037 mmol) in HCl/MeOH (2 M, 2 mL) was stirred at rt for 4 h,then the pH was adjusted to pH>7 with saturated NaHCO₃, and purified byflash column chromatography and preparative TLC to yield the titlecompound as a yellow solid (5 mg, 24% yield). MS (ESI): mass calcd. forC₃₀H₃₀N₆O₄S, 570.7; m/z found, 571.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.16-8.07 (m, 1H), 7.43-7.35 (m, 2H), 7.23-7.12 (m, 2H), 7.11-7.05 (m,2H), 7.04-7.01 (m, 1H), 7.01-6.91 (m, 1H), 5.90-5.75 (m, 1H), 4.26-4.09(m, 2H), 3.97-3.89 (m, 1H), 3.84-3.78 (m, 1H), 3.73-3.55 (m, 2H),3.48-3.41 (m, 1H), 2.60-2.49 (m, 3H), 2.15-2.08 (m, 3H), 2.02-1.87 (m,3H), 1.85-1.73 (m, 1H), 1.67-1.56 (m, 1H).

Example 184:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98, 30 mg, 0.06 mmol), triethylamine (15 mg, 0.015 mmol), andpropanoyl propanoate (15 mg, 0.12 mmol) in DCM (15 mL) was stirred for30 min at rt. The mixture was purified by flash column chromatography toyield the title compound as yellow solid (19 mg, 57% yield). MS (ESI):mass calcd. for C₃₀H₂₉N₅O₄S, 555.6; m/z found, 556.6 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.34-8.28 (m, 1H), 7.51-7.35 (m, 2H), 7.34-7.27 (m, 1H),7.21-7.13 (m, 1H), 711-7.02 (m, 3H), 7.00-6.93 (m, 1H), 6.09-6.01 (m,1H), 4.54-3.83 (m, 3H), 3.16-2.97 (m, 1H), 2.85-2.65 (m, 1H), 2.59-2.36(m, 2H), 2.15-2.09 (m, 3H), 2.09-2.00 (m, 1H), 1.91-1.51 (m, 3H),1.17-1.09 (m, 3H).

Example 185:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-cyclopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 4-cyclopropoxy-2-methyl-1-nitrobenzene

The title compound was prepared using the method from Example 33, StepA, using bromocyclopropane in place of 2-iodopropane.

Step B:(R)-5-(4-Cyclopropoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsB-H in Example 1, and using 4-cyclopropoxy-2-methyl-1-nitrobenzene inplace of 2-methyl-1-nitro-4-phenoxybenzene in Step B, and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step C:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-cyclopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(4-cyclopropoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(80 mg, 0.17 mmol), (E)-2-cyano-3-cyclopropylprop-2-enoic acid(Intermediate 17) (48 mg, 0.35 mmol), HATU (85 mg, 0.22 mmol), anddiisopropylethylamine (44 mg, 0.35 mmol) in DMF (5 mL) was stirred at rtfor 2 h. The mixture was purified by HPLC to yield the title compound asa white solid (27 mg, 27% yield). MS (ESI): mass calcd. for C₃₁H₃₀N₆O₄S,582.7; m/z found, 583.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33-8.27 (m,1H), 7.25-7.20 (m, 1H), 7.14-7.10 (m, 1H), 7.10-7.04 (m, 1H), 6.57-6.49(m, 1H), 6.04-5.99 (m, 1H), 4.14-3.93 (m, 3H), 3.89-3.79 (m, 1H),3.25-3.05 (m, 2H), 2.12 (s, 3H), 2.09-1.95 (m, 2H), 1.93-1.83 (m, 1H),1.82-1.70 (m, 1H), 1.68-1.59 (m, 1H), 1.25-1.15 (m, 2H), 1.01-0.91 (m,1H), 0.87-0.77 (m, 3H), 0.75-0.69 (m, 2H).

Example 186:N-((3S,4S)-4-Fluoro-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-((3S,4S)-4-fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 218, 100 mg, 0.2 mmol) and formaldehyde (0.5 mL, 37 wt. % inH₂O) in MeOH (5 mL) was added NaBH(OAc)₃ (127 mg, 0.597 mmol) and wasstirred at rt for 1 h, concentrated to dryness, and purified by flashcolumn chromatography to yield the title compound as a white solid (86mg, 80% yield). MS (ESI): mass calcd. for C₂₇H₂₄FN₅O₃S, 517.6; m/zfound, 518.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.28 (d, J=5.5 Hz, 1H),7.42-7.35 (m, 2H), 7.35-7.30 (m, 1H), 7.18-7.12 (m, 1H), 7.09-7.01 (m,3H), 6.99-6.92 (m, 1H), 6.04 (d, J=5.5 Hz, 1H), 5.39-5.18 (m, 1H),4.66-4.51 (m, 1H), 3.64-3.53 (m, 1H), 3.43-3.37 (m, 1H), 3.36-3.30 (m,1H), 3.05-2.95 (m, 1H), 2.70 (s, 3H), 2.08 (s, 3H).

Example 187:5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazepan-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:N-(Azepan-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl 4-aminoazepane-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazepan-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-(azepan-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.2 mmol) and formaldehyde (0.4 mL, 37 wt. % in H₂O) in MeOH (5mL) was added NaBH(OAc)₃ (124 mg, 0.585 mmol) and was stirred at rt for1 h, concentrated to dryness, and purified by flash columnchromatography to yield the title compound as a yellow solid (70 mg, 68%yield). MS (ESI): mass calcd. for C₂₉H₂₉N₅O₃S, 527.6; m/z found, 528.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.24 (d, J=5.4 Hz, 1H), 7.45-7.33 (m,2H), 7.32-7.22 (m, 1H), 7.22-12 (m, 1H), 7.11-7.01 (m, 3H), 7.01-6.92(m, 1H), 5.98 (d, J=5.4 Hz, 1H), 4.27-4.15 (m, 1H), 3.09-2.98 (m, 1H),2.96-2.79 (m, 3H), 2.54 (s, 3H), 2.16-2.06 (m, 5H), 2.02-1.87 (m, 2H),1.83-1.70 (m, 2H).

Example 188:(R)—N-(1-(3-Methoxy-2,2-dimethylpropanoyl)piperidin-3-yl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 110 mg, 0.22 mmol) in DMF (3 mL) were added3-methoxy-2,2-dimethylpropanoic acid (44 mg, 0.33 mmol), HATU (100 mg,0.26 mmol), and triethylamine (0.123 mL, 0.880 mmol) and was stirred atrt for 4 h. The reaction mixture was purified by flash columnchromatography to yield the title compound as a yellow solid 50 mg, 36%yield). MS (ESI): mass calcd. for C₃₃H₃₅N₅O₅S, 613.7; m/z found, 614.3[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d, J=5.6, 1H), 7.46-7.36 (m,2H), 7.34-7.26 (m, 1H), 7.20-7.13 (m, 1H), 7.12-7.02 (m, 3H), 7.00-6.91(m, 1H), 6.13-6.02 (m, 1H), 4.44-4.23 (m, 2H), 4.03-3.92 (m, 1H),3.60-3.51 (m, 1H), 3.47-3.39 (m, 1H), 3.36 (s, 3H), 3.01-2.92 (m, 1H),2.92-2.83 (m, 1H), 2.12 (s, 3H), 2.08-2.01 (m, 1H), 1.85-1.79 (m, 1H),1.77-1.65 (m, 1H), 1.63-1.50 (m, 1H), 1.30 (s, 6H).

Example 189:N-(1-Cyanoazepan-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl 4-aminoazepane-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, and using bromocyanide in place ofprop-2-enoyl chloride in step I. MS (ESI): mass calcd. for C₂₉H₂₆N₆O₃S,538.6; m/z found, 539.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d,J=5.6 Hz, 1H), 7.44-7.36 (m, 2H), 7.28 (d, J=8.6 Hz, 1H), 7.21-7.13 (m,1H), 7.12-7.03 (m, 3H), 7.01-6.92 (m, 1H), 6.07 (d, J=5.6 Hz, 1H),4.12-4.00 (m, 1H), 3.50-3.38 (m, 2H), 3.33-3.30 (m, 1H), 3.28-3.24 (m,1H), 2.14-2.08 (m, 4H), 2.05-1.88 (m, 3H), 1.85-1.69 (m, 2H).

Example 190:N—((R)-1-((R)-2,3-Dimethoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: Methyl (2R)-2-hydroxy-3-methoxypropanoate

To a solution of methyl cyclopropanecarboxylate (1.0 g, 9.8 mmol) inMeOH (1 mL) was added Mg₂(SO₃CF₃)₂ (4.05 g, 11.7 mmol) at rt and warmedto 40° C. for 16 h. The reaction mixture was filtered, washed with DCM,and concentrated to dryness to yield the title compound as a colorlessoil (900 mg, 69%).

Step B: Methyl (2R)-2,3-dimethoxypropanoate

To a solution of methyl (2R)-2-hydroxy-3-methoxypropanoate (900 mg, 6.7mmol) in DCM (10 mL) were added methyl iodide (1.90 g, 13.4 mmol) andAg₂O (2.32 g, 10.0 mmol) at rt. The reaction was warmed to 40° C. for 16h, filtered, washed with DCM, and concentrated to dryness to yield thetitle compound as a colorless oil (400 mg, 40%).

Step C: (2R)-2,3-Dimethoxypropanoic acid

A solution of methyl (2R)-2,3-dimethoxypropanoate (400 mg, 2.7 mmol),LiOH.H₂O (454 mg, 10.8 mmol) in dimethoxymethane (4 mL) and H₂O (1 mL)was reacted at rt for 16 h. The pH was adjusted to pH<7, extracted withDCM, concentrated to remove the DCM, which yielded the title compound asa colorless oil as a solution in dimethoxymethane (3.0 g).

Step D:N—((R)-1-((R)-2,3-Dimethoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (2R)-2,3-dimethoxypropanoic acid (50 mg, 0.37 mmol) inDCM (5 mL) was added oxalyl dichloride (2 mL) and reacted at 60° C.overnight. The reaction mixture was concentrated to dryness anddissolved in DCM (5 mL). The mixture was added to solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 80 mg, 0.16 mmol) and triethylamine (40 mg, 0.40 mmol) inDCM (5 mL) and reacted at rt for 30 min. The reaction was quenched withH₂O, extracted with DCM, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by flash columnchromatography to yield the title compound as an off white solid (30 mg,30%). MS (ESI): mass calcd. for C₃₂H₃₃N₅O₆S, 615.7; m/z found, 616.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.41-8.27 (m, 1H), 7.46-7.34 (m, 2H),7.33-7.26 (m, 1H), 7.27-7.17 (m, 1H), 7.15-7.02 (m, 3H), 7.02-6.95 (m,1H), 6.12-6.03 (m, 1H), 4.68-4.47 (m, 3H), 4.41-3.89 (m, 3H), 3.77-3.55(m, 2H), 3.44-3.36 (m, 4H), 3.52-3.12 (m, 1H), 3.01-2.77 (m, 1H),2.19-2.11 (m, 3H), 2.07-2.01 (m, 1H), 1.93-1.81 (m, 1H), 1.78-1.49 (m,2H).

Example 191:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((R)-pyrrolidine-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-butyl3-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carbonyl)pyrrolidine-1-carboxylate

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 300 mg, 0.60 mmol),(3R)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (258 mg, 1.20mmol), HATU (456 mg, 1.20 mmol), and triethylamine (121 mg, 1.20 mmol)in DMF (5 mL) was reacted at rt for 2 h. The reaction was quenched withH₂O (10 mL), extracted with DCM, dried over anhydrous Na₂SO₄, filtered,and concentrated to dryness. The residue was purified by flash columnchromatography to yield the title compound as a yellow solid (350 mg,83% yield).

Step B:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((R)-pyrrolidine-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (R)-tert-butyl3-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carbonyl)pyrrolidine-1-carboxylate(350 mg, 0.50 mmol) in MeOH (5 mL) was added HCl (37%, 2 mL) and wasreacted at rt for 1 h. The reaction was quenched by the addition of asaturated solution of NaHCO₃ (20 mL), extracted with DCM, dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness to yield thetitle compound as a yellow solid (200 mg, 67% yield). MS (ESI): masscalcd. for C₃₂H₃₂N₆O₄S, 596.7; m/z found, 597.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.43 (s, 1H), 8.36-8.30 (m, 1H), 7.44-7.34 (m, 2H), 7.33-7.25(m, 1H), 7.20-7.13 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.92 (m, 1H),6.13-6.03 (m, 1H), 4.52-4.33 (m, 1H), 4.24-3.87 (m, 2H), 3.75-3.61 (m,2H), 3.44-3.31 (m, 3H), 3.09-2.62 (m, 2H), 2.40-2.15 (m, 1H), 2.15-1.99(m, 5H), 1.92-1.50 (m, 3H).

Example 192:N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using (4-aminotetrahydropyran-4-yl)methanol inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₆N₄O₅S,530.6; m/z found, 531.7 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 10.14 (s,1H), 8.35-8.23 (m, 1H), 7.48-7.41 (m, 2H), 7.38-7.30 (m, 1H), 7.24-7.17(m, 1H), 7.16-7.06 (m, 3H), 7.01-6.94 (m, 1H), 6.00-5.86 (m, 1H),5.08-4.90 (m, 1H), 3.71-3.52 (m, 6H), 2.29-2.12 (m, 2H), 2.06 (s, 3H),1.68-1.56 (m, 2H).

Example 193:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-ethoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: Step A: 4-Ethoxy-2-methyl-1-nitrobenzene

To a mixture of 3-methyl-4-nitrophenol (5.0 g, 33 mmol) and K₂CO₃ (13.6g, 98.6 mmol) in DMF (25 mL) was added bromoethane (8.9 g, 82 mmol) andthe reaction was stirred at 80° C. overnight. Water was added to thereaction mixture and a yellow solid was precipitated. The precipitatewas filtered, washed with water, and dried to yield the title compound(4.5 g, 76% yield) as a yellow solid.

Step B:(R)-5-(4-Ethoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsB-H in Example 1, and using 4-ethoxy-2-methyl-1-nitrobenzene in place of2-methyl-1-nitro-4-phenoxybenzene Step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step C:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-ethoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a stirred suspension of(R)-5-(4-ethoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.22 mmol) in DMF (3 mL) were added(E)-2-cyano-3-cyclopropylprop-2-enoic acid (Intermediate 17) (36 mg,0.26 mmol), HATU (100 mg, 0.26 mmol), and diisopropylethylamine (60 mg,0.46 mmol) and was stirred at rt overnight. The reaction mixture wasconcentrated to dryness and the residue was partitioned between ethylacetate and water. The organic layer was separated, shaken with brine,dried over anhydrous Na₂SO₄, and purified by flash column chromatographyto yield the title compound as a brown solid (73 mg, 56% yield). MS(ESI): mass calcd. for C₃₀H₃₀N₆O₄S, 570.7; m/z found, 571.9 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.29 (d, J=5.2 Hz, 1H), 7.26-7.16 (m, 1H),7.01-6.94 (m, 1H), 6.93-6.87 (m, 1H), 6.60-6.47 (m, 1H), 6.04-5.97 (m,1H), 4.27-3.88 (m, 5H), 3.25-3.00 (m, 1H), 2.14-2.09 (m, 3H), 2.09-1.49(m, 6H), 1.46-1.35 (m, 3H), 1.25-1.13 (m, 2H), 1.04-0.70 (m, 2H).

Example 194:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-fluorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 2-fluoroaniline in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₃H₂₀FN₅O₃S, 465.5; m/z found, 466.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.37 (s, 1H), 8.33 (d, J=5.4 Hz,1H), 8.24-8.03 (m, 1H), 7.68-7.54 (m, 2H), 7.54-7.46 (m, 1H), 7.44-7.33(m, 1H), 6.87-6.64 (m, 1H), 6.15-5.97 (m, 2H), 5.65 (d, J=10.6 Hz, 1H),4.55-4.11 (m, 1H), 4.10-3.88 (m, 1H), 3.79-3.69 (br, 1H), 3.14-2.90 (m,1H), 2.83-2.57 (m, 1H), 2.05-1.85 (m, 1H), 1.83-1.52 (m, 2H), 1.52-1.29(m, 1H).

Example 195:(R,Z)—N-(1-(4-Amino-2-cyano-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R,Z)-tert-Butyl(4-cyano-2-methyl-5-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-5-oxopent-3-en-2-yl)carbamate

A solution of((R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 300 mg, 0.53 mmol), tert-butylN-(1,1-dimethyl-2-oxo-ethyl)carbamate (297 mg, 1.59 mmol), piperdine(0.5 mL), acetic acid (0.2 mL), dioxane (15 mL), and 4A molecular sieves(1 g) were added to a flask and stirred at 100° C. for 1 h under N2. Themixture was concentrated to dryness and purified by flash columnchromatography to yield the title compound as a light yellow solid (188mg, 48.2% yield).

Step B:(R,Z)—N-(1-(4-Amino-2-cyano-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (R,Z)-tert-butyl(4-cyano-2-methyl-5-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-5-oxopent-3-en-2-yl)carbamate(188 mg, 0.255 mmol) in MeOH (5 mL) was added concentrated HCl (5 mL)and stirred at rt for 10 min. The mixture was concentrated to dryness,diluted with DCM, washed with saturated NaHCO₃ and brine, concentratedto dryness, and purified by flash column chromatography to yield thetitle compound as a yellow solid (151 mg, 90.6% yield). MS (ESI): masscalcd. for C₃₄H₃₃N₇O₄S, 635.7; m/z found, 636.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.28-8.20 (m, 1H), 7.83-7.63 (m, 1H), 7.42-7.34 (m, 2H),7.28-7.21 (m, 1H), 7.18-7.11 (m, 1H), 7.09-7.00 (m, 3H), 6.98-6.92 (m,1H), 6.01-5.95 (m, 1H), 4.30-3.73 (m, 3H), 3.36-3.25 (m, 2H), 2.14-2.04(m, 4H), 2.01-1.83 (m, 2H), 1.75-1.62 (m, 1H), 1.60-1.46 (m, 6H).

Example 196:(R,E)-N-(1-(3-(1-Aminocyclopropyl)-2-cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R,E)-tert-butyl(1-(2-cyano-3-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-3-oxoprop-1-en-1-yl)cyclopropyl)carbamate

A solution of((R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 150 mg, 0.26 mmol), tert-butylN-(1-formylcyclopropyl)carbamate (147 mg, 0.795 mmol), piperidine (0.3mL), acetic acid (0.1 mL), dioxane (10 mL), and 4A molecular sieves (1g) was stirred at 100° C. for 1 h under N2. The mixture was concentratedto dryness and purified by flash column chromatography to yield thetitle compound as a light yellow solid (153 mg, 78.5% yield).

Step B:(R,E)-N-(1-(3-(1-Aminocyclopropyl)-2-cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (R,E)-tert-butyl(1-(2-cyano-3-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-3-oxoprop-1-en-1-yl)cyclopropyl)carbamate(153 mg, 0.21 mmol) in MeOH (4 mL) was added TFA (1 mL) and was stirredat rt for 20 min. The mixture was concentrated to dryness, diluted withDCM, washed with saturated NaHCO₃ and brine, concentrated to dryness,and purified by flash column chromatography to yield the title compoundas a brown solid (68 mg, 51% yield). MS (ESI): mass calcd. forC₃₄H₃₁N₇O₄S, 633.7; m/z found, 634.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD andDMSO-d₆): δ 8.36-8.18 (m, 1H), 7.59-7.18 (m, 4H), 7.18-6.85 (m, 5H),6.03-5.84 (m, 1H), 4.66-4.39 (m, 1H), 4.12-3.69 (m, 2H), 3.07-2.67 (m,2H), 2.10-1.77 (m, 6H), 1.77-1.48 (m, 3H), 1.39-1.11 (m, 2H).

Example 197:N-((3R,5S)-5-Hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using using Method 1, steps A-H inExample 1, using tert-butyl(3R,5S)-3-amino-5-hydroxypiperidine-1-carboxylate (Intermediate 2) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₄S,515.6; m/z found, 516.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.37-8.27 (m,1H), 7.47-7.35 (m, 2H), 7.35-7.28 (m, 1H), 7.23-7.12 (m, 1H), 7.13-7.03(m, 3H), 7.02-6.94 (m, 1H), 6.07 (d, J=5.6 Hz, 1H), 4.41-4.25 (m, 1H),4.12-4.00 (m, 1H), 3.29-3.19 (m, 2H), 3.14-3.02 (m, 1H), 3.00-2.89 (m,1H), 2.26-2.15 (m, 1H), 2.14-2.07 (m, 3H), 1.90-1.80 (m, 1H).

Example 198:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((R)-tetrahydrofuran-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 90 mg, 0.18 mmol), (3R)-tetrahydrofuran-3-carboxylic acid(88 mg, 0.76 mmol), HATU (168 mg, 0.44 mmol), and triethylamine (45 mg,0.45 mmol) in DMF (5 mL) was reacted at rt for 2 h. The reaction wasquenched by the addition of H₂O (10 mL), extracted with DCM, dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue waspurified by flash column chromatography to yield the title compound as ayellow solid (52 mg, 48% yield). MS (ESI): mass calcd. for C₃₂H₃₁N₅O₅S,597.7; m/z found, 598.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35-8.27 (m,1H), 7.43-7.35 (m, 2H), 7.32-7.28 (m, 1H), 7.19-7.12 (m, 1H), 7.12-7.00(m, 3H), 6.99-6.92 (m, 1H), 6.11-6.00 (m, 1H), 4.52-4.29 (m, 1H),4.21-3.79 (m, 6H), 3.52-3.38 (m, 1H), 3.22-3.00 (m, 1H), 2.87-2.69 (m,1H), 2.39-2.14 (m, 1H), 2.14-2.09 (m, 3H), 2.09-1.97 (m, 2H), 1.88-1.50(m, 3H).

Example 199:(R,E)-N-(1-(3-Cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 100 mg, 0.2 mmol) and (E)-3-cyclopropylprop-2-enoic acid(500 mg, 4.5 mmol) in anhydrous DMF (5 mL) were added HATU (228 mg,0.600 mmol) and diisopropylethylamine (130 mg, 1.0 mmol) and was stirredovernight at rt. The reaction mixture was purified by flash columnchromatography, then preparative TLC to yield the title compound as ayellow solid (41 mg, 34% yield). MS (ESI): mass calcd. for C₃₃H₃₁N₅O₄S,593.7; m/z found, 594.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ9.51-9.41 (m,1H), 8.34 (d, J=5.4 Hz, 1H), 7.42-7.35 (m, 2H), 7.20-7.13 (m, 2H),7.12-7.06 (m, 2H), 7.01-6.98 (m, 1H), 6.97-6.92 (m, 1H), 6.52-6.33 (m,2H), 6.00 (d, J=5.4 Hz, 1H), 4.16-4.06 (m, 1H), 4.01-3.78 (m, 1H),3.63-3.27 (m, 2H), 2.14-2.09 (m, 3H), 2.05-1.92 (m, 1H), 1.81-1.58 (m,5H), 0.96-0.82 (m, 2H), 0.76-0.42 (m, 2H).

Example 200:N-((3S,4R)-4-Hydroxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-((3S,4R)-4-hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 241, 100 mg, 0.2 mmol) and formaldehyde (0.5 mL, 37 wt. % inH₂O) in MeOH (5 mL) was added NaBH(OAc)₃ (127 mg, 0.597 mmol) andstirred at rt overnight, concentrated to dryness, and purified by flashcolumn chromatography to yield the title compound as a yellow solid (53mg, 50% yield). MS (ESI): mass calcd. for C₂₇H₂₅N₅O₄S, 515.6; m/z found,516.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33-8.17 (m, 1H), 7.43-7.33(m, 2H), 7.33-7.23 (m, 1H), 7.18-7.09 (m, 1H), 7.10-7.00 (m, 3H),7.00-6.90 (m, 1H), 6.04-5.93 (m, 1H), 4.57-4.37 (m, 2H), 3.14-2.94 (m,2H), 2.87-2.69 (m, 2H), 2.47 (s, 3H), 2.09 (s, 3H).

Example 201:(R)-5-(4-(2-Cyclopropylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(2-Cyclopropylphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 2-cyclopropylphenol in place of phenol instep A, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)-5-(4-(2-Cyclopropylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(2-cyclopropylphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.19 mmol) in DCM (10 mL) was added formaldehyde (30 mg, 1.0mmol, 37 wt. % in H₂O) and after stirring at rt for 10 min, NaBH(OAc)₃(78 mg, 0.37 mmol) was added. The mixture was stirred at rt overnight,then the pH was adjusted to pH>7 with 2 M aqueous NaOH, and concentratedto dryness. The residue was purified by flash column chromatography toyield the title compound as a yellow solid (45 mg, 44% yield). MS (ESI):mass calcd. for C₃₁H₃₁N₅O₃S, 553.7; m/z found, 554.4 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆ and CD₃OD): δ 8.24 (d, J=5.5, 1H), 7.29-7.20 (m, 1H),7.19-7.06 (m, 2H), 7.02-6.89 (m, 3H), 6.86-6.76 (m, 1H), 5.89 (d, J=5.5,1H), 4.06-3.93 (m, 1H), 2.91-2.76 (m, 1H), 2.70-2.59 (m, 1H), 2.23 (s,3H), 2.08-1.92 (m, 6H), 1.82-1.66 (m, 2H), 1.59-1.48 (m, 1H), 1.43-1.32(m, 1H), 0.90-0.80 (m, 2H), 0.67-0.57 (m, 2H).

Example 202:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 4-aminopyrrolidin-2-one in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₆H₂₁N₅O₄S,499.5; m/z found, 500.7 [M+H]⁺. ¹H NMR (400 MHz, a mixture of CD3OD andDMSO-d6): δ 8.25-8.16 (m, 1H), 7.40-7.32 (m, 2H), 7.27-7.18 (m, 1H),7.15-7.08 (m, 1H), 7.07-7.01 (m, 2H), 7.01-7.98 (m, 1H), 6.92-6.88 (m,1H), 5.93-5.84 (m, 1H), 4.67-4.52 (m, 1H), 3.63-3.57 (m, 1H), 3.25-3.19(m, 1H), 2.58-2.51 (m, 1H), 2.36-2.29 (m, 1H), 2.01 (s, 3H).

Example 203:N-(1,2-Dimethylpiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of5-(2-methyl-4-phenoxyphenyl)-N-(2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 258, 150 mg, 0.29 mmol) and formaldehyde (0.6 mL, 37 wt. % inH₂O) in MeOH (30 mL) was added NaBH(OAc)₃ (186 mg, 0.878 mmol) and wasstirred at rt for 3 h, concentrated to dryness, and purified by flashcolumn chromatography to yield the title compound as a yellow solid (110mg, 71% yield). MS (ESI): mass calcd. for C₂₉H₂₉N₅O₃S, 527.6; m/z found,528.7 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ 8.23 (d, J=5.5 Hz,1H), 7.46-7.32 (m, 2H), 7.27 (d, J=8.5 Hz, 1H), 7.19-7.10 (m, 1H),7.09-6.98 (m, 3H), 6.97-6.85 (m, 1H), 5.89 (d, J=5.4 Hz, 1H), 3.90-3.64(m, 2H), 2.98-2.75 (m, 1H), 2.24 (s, 3H), 2.20-2.11 (m, 1H), 2.03 (s,3H), 1.89-1.72 (m, 2H), 1.69-1.53 (m, 1H), 1.43-1.28 (m, 1H), 1.05 (d,J=6.2 Hz, 3H).

Example 204:(R)—N-(1-Methacryloylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.28 mmol), 2-methylprop-2-enoic acid (52 mg, 0.60mmol), HATU (148 mg, 0.390 mmol), and diisopropylethylamine (77 mg, 0.60mmol) in DMF (5 mL) was stirred at rt for 2 h. The mixture was purifiedby HPLC to yield the title compound as a brown solid (105 mg, 66.1%yield). MS (ESI): mass calcd. for C₃₁H₂₉N₅O₄S, 567.7; m/z found, 568.7[M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ 8.27-8.22 (m, 1H),7.38-7.31 (m, 2H), 7.31-7.24 (m, 1H), 7.14-7.07 (m, 1H), 7.07-6.98 (m,3H), 6.94-6.87 (m, 1H), 5.97-5.91 (m, 1H), 5.17-4.93 (m, 2H), 4.05-3.89(m, 1H), 3.86-3.74 (m, 2H), 3.08-2.62 (m, 2H), 2.05-1.99 (m, 3H),1.96-1.88 (m, 1H), 1.84 (s, 3H), 1.78-1.69 (m, 1H), 1.67-1.58 (m, 1H),1.49-1.39 (m, 1H).

Example 205:N-(1-(Cyclopropanecarbonyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 1-(cyclopropylcarbonyl)-3-piperidinamine HClin place of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₁H₂₉N₅O₄S,567.7; m/z found, 568.0 [M+H]⁺. ¹H NMR (500 MHz, Methanol-d4) δ 8.34 (d,J=5.5 Hz, 1H), 7.46-7.36 (m, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.21-7.13 (m,1H), 7.13-7.03 (m, 3H), 6.98 (dd, J=8.5, 2.8 Hz, 1H), 6.09 (d, J=5.5 Hz,1H), 4.51 (d, J=63.3 Hz, 1H), 4.34 (s, 1H), 4.20 (d, J=13.6 Hz, 1H),3.97 (d, J=38.8 Hz, 1H), 3.30-3.15 (m, 1H), 2.99-2.81 (m, 1H), 2.13 (s,3H), 2.00 (s, 1H), 1.95-1.08 (m, 3H), 0.99-0.69 (m, 4H).

Example 206:5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazepan-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:N-(Azepan-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl 3-aminoazepane-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazepan-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-(azepan-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.2 mmol) and formaldehyde (0.3 mL, 37 wt. % in H₂O) in MeOHwas added NaBH(OAc)₃ (124 mg, 0.585 mmol) and stirred at rt for 1 h,concentrated to dryness, and purified by flash column chromatography toyield the title compound as a white solid (70 mg, 63% yield). MS (ESI):mass calcd. for C₂₉H₂₉N₅O₃S, 527.6; m/z found, 528.5 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.50 (s, 1H), 8.31 (d, J=5.6 Hz, 1H), 7.42-7.36 (m, 2H),7.31-7.27 (m, 1H), 7.19-7.12 (m, 1H), 7.11-7.03 (m, 3H), 6.97 (dd,J=8.6, 2.8 Hz, 1H), 6.06 (d, J=5.6 Hz, 1H), 4.31-4.21 (m, 1H), 3.43-3.30(m, 2H), 3.27-3.12 (m, 2H), 2.84 (s, 3H), 2.15-2.04 (m, 1H), 2.08 (s,3H), 2.01-1.83 (m, 4H), 1.74-1.62 (m, 1H).

Example 207:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((S)-tetrahydrofuran-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 120 mg, 0.24 mmol), (3S)-tetrahydrofuran-3-carboxylic acid(100 mg, 0.86 mmol), HATU (150 mg, 0.40 mmol), and triethylamine (80 mg,0.79 mmol) in DMF (5 mL) was reacted at rt for 2 h. The reaction wasquenched with H₂O (10 mL), extracted with DCM, dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby flash column chromatography to yield the title compound as an offwhite solid (57 mg, 40% yield). MS (ESI): mass calcd. for C₃₂H₃₁N₅O₅S,597.7; m/z found, 598.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32-8.27 (m,1H), 7.42-7.29 (m, 3H), 7.19-7.09 (m, 1H), 7.09-7.00 (m, 3H), 6.97-6.90(m, 1H), 6.04-5.98 (m, 1H), 4.60-4.31 (m, 1H), 4.26-4.08 (m, 1H),3.94-3.85 (m, 1H), 3.85-3.66 (m, 4H), 3.52-3.37 (m, 1H), 3.15-2.92 (m,1H), 2.81-2.59 (m, 1H), 2.15-1.97 (m, 6H), 1.89-1.73 (m, 1H), 1.73-1.41(m, 2H).

Example 208:N-((3S,4R)-4-Methoxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-((3S,4R)-4-methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 211, 100 mg, 0.19 mmol) and formaldehyde (0.4 mL, 37 wt. % inH₂O) in MeOH (5 mL) was added NaBH(OAc)₃ (123 mg, 0.582 mmol) and wasstirred at rt for 1 h. The reaction mixture was concentrated to drynessand purified by flash column chromatography to yield the title compoundas a yellow solid (54 mg, 52% yield). MS (ESI): mass calcd. forC₂₈H₂₇N₅O₄S, 529.6; m/z found, 530.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD andDMSO-d₆): δ 8.23 (d, J=5.4 Hz, 1H), 7.41-7.28 (m, 2H), 7.28-7.18 (m,1H), 7.14-7.06 (m, 1H), 7.06-6.95 (m, 3H), 6.94-6.85 (m, 1H), 5.94 (d,J=5.4 Hz, 1H), 4.60-4.51 (m, 1H), 3.96-3.86 (m, 1H), 3.27 (s, 3H),2.92-2.78 (m, 2H), 2.71-2.59 (m, 2H), 2.32 (s, 3H), 2.03 (s, 3H).

Example 209:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 5-chloro-1,3-benzodioxol-4-amine and2,4-dichloropyridine-3-carbonitrile in place of2-methyl-4-phenoxyaniline and 2-chloro-4-iodopyridine-3-carbonitrile instep C, and using tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₃H₁₈ClN₅O₅S,511.9; m/z found, 512.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.37 (d,J=5.5 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.70-6.52(m, 1H), 6.32-6.23 (m, 2H), 6.13-6.07 (m, 2H), 5.82-5.67 (m, 1H),4.67-4.57 (m, 1H), 4.01-3.51 (m, 4H), 2.40-2.21 (m, 1H), 2.19-2.03 (m,1H).

Example 210:(R)-5-(2-Methyl-4-(m-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-Methyl-4-(m-tolyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using m-cresol in place of phenol in step A, andusing tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)-5-(2-Methyl-4-(m-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-(m-tolyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(88 mg, 0.17 mmol) in DCM (5 mL) was added formaldehyde (0.5 mL, 37 wt.% in H₂O) and NaBH(OAc)₃ (73 mg, 0.34 mmol) and stirred at rt for 4 h.The mixture was diluted with DCM (50 mL), MeOH (5 mL), and water (30mL). The organic layer was collected, concentrated to dryness, andpurified by flash column chromatography to yield the title compound as ayellow solid (62 mg, 65% yield). MS (ESI): mass calcd. for C₂₉H₂₉N₅O₃S,527.6; m/z found, 528.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 8.26 (d,J=5.3 Hz, 1H), 8.05 (br, 1H), 7.33-7.26 (m, 2H), 7.05-7.01 (m, 1H),7.00-6.97 (m, 1H), 6.95-6.90 (m, 2H), 6.89-6.85 (m, 1H), 5.88 (d, J=5.4Hz, 1H), 3.95-3.87 (m, 1H), 2.84-2.78 (m, 1H), 2.70-2.61 (m, 1H), 2.30(s, 3H), 2.18 (s, 3H), 2.02 (s, 3H), 1.93-1.83 (m, 2H), 1.79-1.73 (m,1H), 1.69-1.63 (m, 1H), 1.54-1.45 (m, 1H), 1.35-1.27 (m, 1H).

Example 211:N-((3S,4R)-4-Methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using steps A-H in Example 1, and usingtert-butyl (3S,4R)-3-amino-4-methoxypyrrolidine-1-carboxylate(Intermediate 11) in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₄S, 515.6; m/z found, 516.3[M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ 8.29 (d, J=5.5 Hz, 1H),7.43-7.30 (m, 2H), 7.26 (d, J=8.6 Hz, 1H), 7.15-7.08 (m, 1H), 7.07-6.99(m, 3H), 6.92 (dd, J=8.6, 2.8 Hz, 1H), 6.00 (d, J=5.5 Hz, 1H), 4.67-4.60(m, 1H), 4.10-4.03 (m, 1H), 3.53-3.45 (m, 2H), 3.36 (s, 3H), 3.35-3.27(m, 2H), 2.04 (s, 3H).

Example 212:(R,E)-N-(1-(2-Cyano-4-(ethylamino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 3-Bromo-3-methylbutanal

To a solution of 3-methylbutanal (1.0 g, 12 mmol) in Et₂O (10 mL) wasslowly added bromine-1,4-dioxane complex (1.44 g, 5.81 mmol) whilecooling with ice water. The reaction mixture was stirred at rtovernight, then 10% aqueous Na₂S₂O₄ was added. After stirring at rt for30 min, the mixture was extracted with Et₂O. The organic layer waswashed with brine, dried over anhydrous MgSO₄, filtered, andconcentrated to dryness to yield the title compound as a yellow liquid(1.1 g, 56%)

Step B: 3-(Ethylamino)-3-methylbutanal

To a solution of 3-bromo-3-methylbutanal (650 mg, 3.94 mmol) in Et₂O (10mL) was added ethyl amine (0.773 mL, 11.8 mmol) while cooling withice-water. The reaction mixture was stirred at rt overnight, thenconcentrated to dryness and the residue used in next step withoutpurification.

Step C:(R,E)-N-(1-(2-Cyano-4-(ethylamino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 98 mg, 0.17 mmol), 3-(ethylamino)-3-methylbutanal (60 mg,0.52 mmol), and piperidine (0.0085 mL, 0.086 mmol) in CH₃CN (5 mL) wasstirred at 60° C. overnight, concentrated to dryness, and the residuepurified by flash column chromatography to yield the title compound as ayellow solid (20 mg, 17% yield). MS (ESI): mass calcd. for C₃₆H₃₇N₇O₄S,663.8; m/z found, 664.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.12-8.03 (m,1H), 7.63-7.51 (m, 1H), 7.42-7.35 (m, 2H), 7.19-7.12 (m, 2H), 7.11-7.07(m, 2H), 7.06-7.02 (m, 1H), 6.98-6.93 (m, 1H), 5.84-5.78 (m, 1H),4.05-3.95 (m, 1H), 3.76-3.69 (m, 1H), 3.64-3.56 (m, 2H), 3.54-3.45 (m,1H), 3.24-3.17 (m, 1H), 2.16-2.08 (m, 5H), 2.08-1.97 (m, 2H), 1.75-1.70(m, 1H), 1.58-1.45 (m, 6H), 1.18-1.12 (m, 3H).

Example 213:(R)—N-(1-Cyclopropylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.30 mmol), (1-ethoxycyclopropoxy)trimethylsilane(209 mg, 1.20 mmol), NaBH₃CN (38 mg, 0.60 mmol), and acetic acid (2drops) in MeOH (10 mL) was heated at 55° C. overnight. The product waspurified by flash column chromatography to yield the title compound as awhite solid (76 mg, 41% yield). MS (ESI): mass calcd. for C₃₀H₂₉N₅O₃S,539.6; m/z found, 540.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34-8.30 (m,1H), 8.21 (s, 1H), 7.43-7.36 (m, 2H), 7.31-7.26 (m, 1H), 7.19-7.13 (m,1H), 7.11-7.03 (m, 3H), 6.99-6.94 (m, 1H), 6.09-6.06 (m, 1H), 4.20-4.09(m, 1H), 4.34-4.30 (m, 1H), 3.16-3.06 (m, 1H), 2.66-2.53 (m, 2H),2.22-2.12 (m, 1H), 2.11 (s, 3H), 1.98-1.80 (m, 2H), 1.74-1.52 (m, 2H),0.71-0.59 (m, 4H).

Example 214:(R)-5-(4-(3-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(3-Fluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 3-fluorophenol in place of phenol in step A,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)-5-(4-(3-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(3-fluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(96 mg, 0.19 mmol) in DCM (5 mL) were added formaldehyde (0.5 mL, 37 wt.% in H₂O) and NaBH(OAc)₃ (78 mg, 0.37 mmol) and was stirred at rt for 4h. To the mixture was added DCM (50 mL), MeOH (5 mL), and water (30 mL)and the organic layer was collected, concentrated to dryness, andpurified by flash column chromatography to yield the title compound as ayellow solid (58 mg, 56% yield). MS (ESI): mass calcd. for C₂₈H₂₆FN₅O₃S,531.6; m/z found, 532.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 8.24 (d,J=5.2 Hz, 1H), 8.11 (br, 1H), 7.47-7.39 (m, 1H), 7.38-7.28 (m, 1H),7.16-7.08 (m, 1H), 7.05-6.95 (m, 3H), 6.94-6.88 (m, 1H), 5.90 (d, J=5.1Hz, 1H), 3.95-3.87 (m, 1H), 2.84-2.77 (m, 1H), 2.69-2.60 (m, 1H), 2.18(s, 3H), 2.03 (s, 3H), 1.95-1.84 (m, 2H), 1.80-1.71 (m, 1H), 1.70-1.62(m, 1H), 1.53-1.43 (m, 1H), 1.36-1.25 (m, 1H).

Example 215:(R)-5-(2-Fluoro-4-phenoxyphenyl)-N-(1-(3-methoxypropanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-Fluoro-1-nitro-4-phenoxybenzene

To a solution of 3-fluoro-4-nitrophenol (2.0 g, 13 mm01), phenylboronicacid (2.33 g, 19.1 mmol), Cu(OAc)₂ (4.62 g, 25.5 mmol), andtriethylamine (6.44 g, 6.37 mmol) in DCM (60 mL) was added 4A molecularsieves (powder<50 μm, 2 g). The mixture was stirred at rt under N₂overnight, then filtered, concentrated to dryness, and purified by flashcolumn chromatography to yield the title compound as a yellow solid (2.7g, 91% yield).

Step B:(R)-5-(2-Fluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsB-H in Example 1, and using 2-fluoro-1-nitro-4-phenoxybenzene in placeof 2-methyl-1-nitro-4-phenoxybenzene in step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step C:(R)-5-(2-Fluoro-4-phenoxyphenyl)-N-(1-(3-methoxypropanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-fluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(150 mg, 0.30 mmol), 3-methoxypropanoic acid (27 mg, 0.26 mmol), HATU(227 mg, 0.596 mmol), and triethylamine (60 mg, 0.60 mmol) in DMF (4 mL)was stirred at rt for 2 h, then purified by flash column chromatographyto yield the title compound as a white solid (103 mg, 58.1% yield). MS(ESI): mass calcd. for C₃₀H₂₈FN₅O₅S, 589.6; m/z found, 590.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 10.39 (s, 1H), 8.34 (d, J=5.5 Hz, 1H),8.22-7.89 (m, 1H), 7.65-7.51 (m, 1H), 7.51-7.40 (m, 2H), 7.30-7.22 (m,1H), 7.21-7.09 (m, 3H), 6.99-6.89 (m, 1H), 6.17 (d, J=5.4 Hz, 1H),4.49-4.08 (m, 1H), 3.97-3.62 (m, 2H), 3.58-3.46 (m, 2H), 3.22-3.15 (m,3H), 3.05-2.80 (m, 1H), 2.68-2.49 (m, 3H), 1.98-1.83 (m, 1H), 1.81-1.51(m, 2H), 1.49-1.26 (m, 1H).

Example 216:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-G in Example 1, and using 2-methylaniline in place of2-methyl-4-phenoxyaniline for step C, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₄H₂₃N₅O₃S,461.5; m/z found, 462.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.29 (d,J=5.5, 1H), 7.48-7.39 (m, 3H), 7.35-7.30 (m, 1H), 6.86-6.71 (m, 1H),6.25-6.14 (m, 1H), 5.96 (d, J=5.5, 1H), 5.76-5.67 (m, 1H), 4.56-4.26 (m,1H), 4.21-3.90 (m, 2H), 3.20-3.11 (m, 1H), 2.65-2.82 (m, 1H), 2.16 (s,3H), 2.09-2.01 (m, 1H), 1.90-1.82 (m, 1H), 1.80-1.22 (m, 1H), 1.63-1.52(m, 1H).

Example 217:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(2-(2-oxoimidazolidin-1-yl)ethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G in Example 1, and using1-(2-aminoethyl)imidazolidin-2-one in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₄N₆O₄S, 528.6; m/z found, 528.9[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 9.55 (s, 1H), 8.32 (s, 1H), 7.44-7.35(m, 2H), 7.23-7.15 (m, 3H), 7.14-7.07 (m, 2H), 7.00 (d, J=2.7 Hz, 1H),6.99-6.91 (m, 1H), 5.97 (d, J=5.2 Hz, 1H), 4.94 (s, 1H), 3.70-3.56 (m,4H), 3.56-3.40 (m, 4H), 2.13 (s, 3H).

Example 218:N-((3S,4S)-4-Fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using tert-butyl(3S,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₆H₂₂FN₅O₃S, 503.5; m/z found, 504.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.26 (d, J=5.5 Hz, 1H), 7.46-7.35 (m,2H), 7.28 (d, J=8.6 Hz, 1H), 7.19-7.12 (m, 1H), 7.12-0.02 (m, 3H),7.00-6.92 (m, 1H), 6.01 (d, J=5.5 Hz, 1H), 5.28-5.11 (m, 1H), 4.56-4.46(m, 1H), 3.49-3.42 (m, 1H), 3.41-3.34 (m, 1H), 3.25-3.15 (m, 1H),3.06-2.99 (m, 1H), 2.11 (s, 3H).

Example 219:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 90 mg, 0.18 mmol), tetrahydropyran-4-carboxylic acid (88mg, 0.67 mmol), HATU (168 mg, 0.442 mmol), and triethylamine (45 mg,0.45 mmol) in DMF (5 mL) was reacted at rt for 2 h. The reaction wasquenched by the addition of H₂O (10 mL), extracted with DCM, dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue waspurified by flash column chromatography to give the title compound as anoff white solid (57 mg, 53% yield). MS (ESI): mass calcd. forC₃₃H₃₃N₅O₅S, 611.7; m/z found, 612.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.35-8.31 (m, 1H), 7.43-7.36 (m, 2H), 7.35-7.27 (m, 1H), 7.22-7.12 (m,1H), 7.11-7.02 (m, 3H), 7.00-6.92 (m, 1H), 6.10-6.05 (m, 1H), 4.56-4.26(m, 1H), 4.21-3.81 (m, 4H), 3.61-3.38 (m, 2H), 3.20-2.93 (m, 2H),2.83-2.67 (m, 1H), 2.14-2.08 (m, 3H), 2.08-1.98 (m, 1H), 1.91-1.82 (m,1H), 1.82-1.63 (m, 4H), 1.63-1.48 (m, 2H).

Example 220:(R)-5-(4-(2-Hydroxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: Methyl3-amino-4-((4-(2-((tert-butyldimethylsilyl)oxy)phenoxy)-2-methylphenyl)amino)thieno[2,3-b]pyridine-2-carboxylate

A solution of4-((4-(2-((tert-butyldimethylsilyl)oxy)phenoxy)-2-methylphenyl)amino)-2-chloronicotinonitrile(Intermediate 25) (2.54 g, 5.45 mmol), methyl 2-sulfanylacetate (1.157g, 10.90 mmol), and NaOMe (589 mg, 10.9 mmol) in MeOH (15 mL) wasstirred at reflux for 16 hours. The mixture was concentrated to drynessand dispersed between DCM and water. The organic layer was collected,concentrated to dryness, and was used in the next step without furtherpurification (1.345 g, 46% yield).

Step B: Methyl5-(4-(2-((tert-butyldimethylsilyl)oxy)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

A solution of methyl4-((4-(2-((tert-butyldimethylsilyl)oxy)phenoxy)-2-methylphenyl)amino)-3-methylthieno[2,3-b]pyridine-2-carboxylate(1.345 g, 2.511 mmol) and CDI (1.221 g, 7.530 mmol) in dioxane (15 mL)was stirred at reflux for 3 hours, concentrated to dryness, and purifiedby normal phase flash column chromatography (SiO₂) to give the titlecompound (1.03 g, 73.0% yield).

Step C:5-(4-(2-Hydroxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

A solution of methyl5-(4-(2-((tert-butyldimethylsilyl)oxy)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(1.03 g, 1.83 mmol) and LiOH.H₂O (385 mg, 9.18 mmol) in THF/MeOH/water(10 mL/4 mL/4 mL) was stirred at reflux for 4 hours, concentrated undervacuum to half volume, and the pH was adjusted to pH=6 using AcOH. Theprecipitate was collected by filtration and dried under vacuum to givethe title compound (702 mg, 88.0% yield), which was used in the nextstep without further purification.

Step D:(R)-5-(4-(2-Hydroxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of5-(4-(2-hydroxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (702 mg, 1.62 mmol) and tert-butyl(3R)-3-aminopiperidine-1-carboxylate (649 mg, 3.24 mmol) in DMF (3 mL)were added HATU (1.232 g, 3.240 mmol) and triethylamine (328 mg, 3.24mmol) and was stirred at room temperature for 4 hours. The mixture wasconcentrated to dryness and the residue dissolved in MeOH (20 mL) andconcentrated HCl (2 mL). The mixture was concentrated to dryness anddispersed between DCM and 10% aqueous NH₃, the organic layer collected,concentrated to dryness, and used in the next step without furtherpurification (610 mg, 73% yield).

Step E:(R)-5-(4-(2-Hydroxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(2-hydroxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(316 mg, 0.613 mmol) in DCM (10 mL) were added formaldehyde (1 mL, 37wt. % in H₂O) and NaBH(OAc)₃ (260 mg, 1.23 mmol) and was stirred at roomtemperature for 4 hours. To the mixture were added DCM (50 mL), MeOH (5mL), water (30 mL), and an aqueous NH₄OH solution (2 mL). The organiclayer was separated, concentrated to dryness, and purified by normalphase flash column chromatography (SiO₂) to give the title compound asyellow solid (82 mg, 25% yield). MS (ESI): mass calcd. for C₂₈H₂₇N₅O₄S,529.6; m/z found, 530.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 9.64 (br,1H), 8.36-8.24 (m, 1H), 8.14-7.94 (m, 1H), 7.30-7.22 (m, 1H), 7.12-7.04(m, 2H), 7.03-6.97 (m, 1H), 6.93-6.83 (m, 2H), 6.83-6.75 (m, 1H),5.94-5.82 (m, 1H), 3.98-3.91 (m, 1H), 2.87-2.81 (m, 1H), 2.71-2.65 (m,1H), 2.22 (s, 3H), 2.02 (s, 3H), 1.97-1.88 (m, 2H), 1.81-1.75 (m, 1H),1.73-1.66 (m, 1H), 1.56-1.48 (m, 1H), 1.39-1.30 (m, 1H).

Example 221:(R,E)-N-(1-(3-Ethoxyacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (E)-3-Ethoxyprop-2-enoic acid

A solution of ethyl (E)-3-ethoxyprop-2-enoate (5.0 g, 0.035 mmol) wasdissolved in a 2 M NaOH (40 mL) solution and refluxed for 4 hours. Themixture was cooled to rt, the pH adjusted to pH 3 with 4 M aqueous HCl,and extracted with ethyl acetate. The organic phase was treated withactivated charcoal and sodium sulphate, filtered, and concentrated todryness to give the title compound as a tan solid (1.8 g, 44% yield).

Step B:(R,E)-N-(1-(3-Ethoxyacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (EZ)-3-ethoxyprop-2-enoic acid (81 mg, 0.70 mmol) andthionyl chloride (1 mL) was refluxed for 2 h and concentrated to drynessto give the (EZ)-3-ethoxyprop-2-enoyl chloride crude product. To a coldstirred solution of (EZ)-3-ethoxyprop-2-enoyl chloride in DCM (5 mL) wasadded(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 300 mg, 0.60 mmol) and triethylamine (182 mg, 1.80 mmol).The mixture was warmed and stirred at rt for 1 h. Water was added andthe solution was extracted with DCM. The organic layer was concentratedto dryness and the resulting residue was purified by flash columnchromatography to give the title compound as a yellow solid (80 mg, 22%yield). MS (ESI): mass calcd. for C₃₂H₃₁N₅O₅S, 597.7; m/z found, 598.5[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35-8.20 (m, 1H), 7.60-7.42 (m, 1H),7.41-7.30 (m, 3H), 7.19-7.10 (m, 1H), 7.07-6.98 (m, 3H), 6.98-6.90 (m,1H), 6.09-5.98 (m, 1H), 5.88-5.76 (m, 1H), 4.63-4.13 (m, 1H), 4.09-3.72(m, 4H), 3.18-3.01 (m, 1H), 3.00-2.66 (m, 1H), 2.12-2.04 (m, 3H),2.03-1.95 (m, 1H), 1.86-1.75 (m, 1H), 1.74-1.62 (m, 1H), 1.57-1.43 (m,1H), 1.33-1.21 (m, 3H).

Example 222:(R)-5-(2-Fluoro-6-methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps C-G in Example 1, and using2-fluoro-6-methyl-4-phenoxyaniline (Intermediate 9) in place of2-methyl-4-phenoxyaniline in step C, and using(3R)-1-methylpiperidin-3-amine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₈H₂₆FN₅O₃S, 531.6; m/z found, 532.3[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.31 (d, J=5.6 Hz, 1H), 7.48-7.40 (m,2H), 7.26-7.18 (m, 1H), 7.16-7.08 (m, 2H), 6.90-6.83 (m, 1H), 6.81-6.72(m, 1H), 6.10 (d, J=5.5 Hz, 1H), 4.26-4.11 (m, 1H), 3.05-2.92 (m, 1H),2.83-2.69 (m, 1H), 2.38-2.35 (m, 3H), 2.30-2.18 (m, 2H), 2.15 (s, 3H),1.97-1.78 (m, 2H), 1.74-1.62 (m, 1H), 1.59-1.44 (m, 1H).

Example 223:(R)-5-(4-(2-Isopropylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(2-isopropylphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using 2-isopropylphenol in placeof phenol in step A, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)-5-(4-(2-Isopropylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(2-isopropylphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.19 mmol) and formaldehyde (0.3 mL, 37 wt. % in H₂O) in MeOH(6 mL) was added NaBH(OAc)₃ (118 mg, 0.555 mmol) and was stirred at rtfor 1 h, concentrated to dryness, and purified by flash columnchromatography to give the title compound as a white solid (63 mg, 54%yield). MS (ESI): mass calcd. for C₃₁H₃₃N₅O₃S, 555.7; m/z found, 556.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.49 (s, 1H), 8.35-8.21 (m, 1H),7.46-7.34 (m, 1H), 7.35-7.25 (m, 1H), 7.24-7.14 (m, 2H), 7.01-6.92 (m,2H), 6.91-6.82 (m, 1H), 6.08-5.96 (m, 1H), 4.35-4.22 (m, 1H), 3.52-3.38(m, 1H), 3.28-3.17 (m, 2H), 2.90-2.66 (m, 5H), 2.14-2.06 (m, 3H),2.05-1.94 (m, 2H), 1.90-1.78 (m, 1H), 1.72-1.60 (m, 1H), 1.22 (d, J=6.9Hz, 6H).

Example 224:N-((3R,5R)-5-Methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using tert-butyl(3R,5R)-3-amino-5-methoxypiperidine-1-carboxylate (Intermediate 6) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₇N₅O₄S,529.6; m/z found, 530.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.24 (d,J=5.6 Hz, 1H), 7.45-7.35 (m, 2H), 7.29-7.23 (m, 1H), 7.19-7.12 (m, 1H),7.11-7.02 (m, 3H), 7.01-6.93 (m, 1H), 5.98 (d, J=5.6 Hz, 1H), 4.41-4.25(m, 1H), 3.62-3.54 (m, 1H), 3.41-3.37 (m, 3H), 3.22-3.13 (m, 1H),3.10-3.01 (m, 1H), 2.80-2.72 (m, 1H), 2.70-2.59 (m, 1H), 2.28-2.15 (m,1H), 2.11 (s, 3H), 1.87-1.75 (m, 1H).

Example 225:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-methylbut-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.30 mmol) and 3-methylbut-2-enoic acid (60 mg,0.60 mmol) in DMF (2 mL) were added HATU (228 mg, 0.600 mmol) andtriethylamine (61 mg, 0.60 mmol) and was stirred at rt for 4 hours. Themixture was purified by flash column chromatography, then by preparativeTLC to give the title compound as a yellow solid (117 mg, 66.0% yield).MS (ESI): mass calcd. for C₃₂H₃₁N₅O₄S, 581.7; m/z found, 582.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.22 (s, 1H), 8.30 (d, J=5.2 Hz, 1H),8.11-8.00 (m, 1H), 7.47-7.38 (m, 2H), 7.38-7.32 (m, 1H), 7.20-7.14 (m,1H), 7.13-7.02 (m, 3H), 6.99-6.92 (m, 1H), 5.94 (d, J=5.1 Hz, 1H),5.90-5.81 (m, 1H), 4.44-4.10 (m, 1H), 3.90-3.69 (m, 2H), 3.05-2.85 (m,1H), 2.69-2.52 (m, 1H), 2.03 (s, 3H), 1.95-1.86 (m, 1H), 1.79-1.72 (m,6H), 172-1.51 (m, 2H), 1.42-1.30 (m, 1H).

Example 226:(R)-5-(4-(3-(Methoxymethyl)phenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 4-[3-(Methoxymethyl)phenoxy]-2-methylaniline

To a solution of 1-bromo-3-(methoxymethyl)benzene (2.6 g, 13 mmol) and4-amino-3-methylphenol (1.6 g, 13 mmol) in CH₃CN (50 mL) were addedK₂CO₃ (7.10 g, 51.5 mmol), (1R,2R)—N¹,N²-dimethylcyclohexane-1,2-diamine(369 mg, 2.59 mmol), and CuI (247 mg, 1.30 mmol) and it was charged withN₂ and was stirred at 80° C. overnight. The reaction mixture wasconcentrated to dryness, extracted with EtOAc/H₂O, the organic layer wascollected and purified by flash column chromatography to give the titlecompound as a black solid (500 mg, 16% yield).

Step B:(R)-5-(4-(3-(Methoxymethyl)phenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps C-G in Example 1, and using4-[3-(methoxymethyl)phenoxy]-2-methylaniline in place of2-methyl-4-phenoxyaniline in step C, and using(3R)-1-methylpiperidin-3-amine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₃₁N₅O₄S, 557.7; m/z found, 558.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.71-9.44 (m, 1H), 8.33 (d, J=5.4 Hz,1H), 8.25-8.04 (m, 1H), 7.40-7.30 (m, 1H), 7.23-7.11 (m, 2H), 7.09 (s,1H), 7.04-6.97 (m, 2H), 6.97-6.90 (m, 1H), 5.95 (d, J=5.4 Hz, 1H),4.79-4.61 (m, 1H), 4.46 (s, 2H), 3.59-3.47 (m, 1H), 3.40 (s, 3H),3.73-3.41 (m, 2H), 2.83 (s, 3H), 2.76-2.61 (m, 1H), 2.60-2.28 (m, 1H),2.18-1.99 (m, 4H), 2.00-1.83 (m, 1H), 1.83-1.62 (m, 1H).

Example 227:(R)-5-(2-Methyl-4-(2-(trifluoromethoxy)phenoxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-Methyl-4-(2-(trifluoromethoxy)phenoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using 2-(trifluoromethoxy)phenolin place of phenol in step A, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)-5-(2-Methyl-4-(2-(trifluoromethoxy)phenoxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-(2-(trifluoromethoxy)phenoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(107 mg, 0.183 mmol) in DCM (5 mL) were added formaldehyde (0.5 mL, 37wt. % in H₂O) and NaBH(OAc)₃ (78 mg, 0.37 mmol) and was stirred at rtfor 4 hours. To the mixture were added DCM (50 mL), MeOH (5 mL), andwater (30 mL). The organic layer was collected, concentrated to dryness,and purified by flash column chromatography to give the title compoundas a yellow solid (66 mg, 60% yield). MS (ESI): mass calcd. forC₂₉H₂₆F₃N₅O₄S, 597.6; m/z found, 598.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d6): δ 8.26 (d, J=5.5 Hz, 1H), 8.12-7.99 (m, 1H), 7.58-7.50 (m,1H), 7.46-7.40 (m, 1H), 7.37-7.32 (m, 1H), 7.32-7.27 (m, 1H), 7.26-7.22(m, 1H), 7.11-7.07 (m, 1H), 6.98-6.93 (m, 1H), 5.88 (d, J=5.5 Hz, 1H),3.95-3.88 (m, 1H), 2.87-2.87 (m, 1H), 2.72-2.61 (m, 1H), 2.20 (s, 3H),2.04 (s, 3H), 1.96-1.84 (m, 2H), 1.79-1.72 (m, 1H), 1.70-1.63 (m, 1H),1.54-1.44 (m, 1H), 1.37-1.27 (m, 1H).

Example 228:(R,Z)—N-(1-(3-Cyclopropyl-2-fluoroacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: Ethyl 2-diethoxyphosphoryl-2-fluoroacetate

A solution of ethyl 2-bromo 2-fluoroacetate (5.0 g, 27 mmol) andtriethylphosphite (13 mL) was heated at 130° C. for 23 h. The resultingmixture was distilled under reduced pressure (1.4 mbar, 75-110° C.) togive the title compound as a yellowish oil (6 g, 92%).

Step B: (Z)-3-Cyclopropyl-2-fluoroprop-2-enoic acid

A solution of ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (2.0 g, 8.3mmol) in THF (5 mL) was cooled to 0° C. in an ice-batch. NaH (198 mg,8.26 mmol) was added and stirred for 30 min, thencyclopropanecarbaldehyde (0.579 g, 8.26 mmol) was slowly added to thereaction mixture and the reaction mixture was allowed to warm to rt for2 h. The reaction was worked up by the addition of DCM and water. Theorganic layer was separated and washed with brine, dried over anhydrousMgSO₄, and concentrated to dryness. The residue was dissolved in dioxane(5 mL), and water (5 mL) and NaOH (1.321 g, 33.03 mmol) were added andstirred for 10 min, then it was acidified with 2 M aqueous HCl to pH ˜2and extracted with DCM. The organic layers were washed with brine, driedover anhydrous MgSO₄, and concentrated to dryness to give the titlecompound (0.72 g, 67% yield).

Step C:(R,Z)—N-(1-(3-Cyclopropyl-2-fluoroacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.28 mmol), (Z)-3-cyclopropyl-2-fluoroprop-2-enoicacid (73 mg, 0.56 mmol), HATU (213 mg, 0.560 mmol), and triethylamine(142 mg, 1.40 mmol) in DMF (3 mL) was stirred at rt for 2 h. Thereaction mixture was purified by flash column chromatography to give thetitle compound as a white solid (50 mg, 29% yield). MS (ESI): masscalcd. for C₃₃H₃₀FN₅O₄S, 611.7; m/z found, 612.5 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 10.21 (s, 1H), 8.33 (d, J=5.5 Hz, 1H), 8.07 (s, 1H),7.49-7.40 (m, 2H), 7.39-7.33 (m, 1H), 7.24-7.15 (m, 1H), 7.15-7.05 (m,3H), 7.02-6.93 (m, 1H), 5.97 (d, J=5.5 Hz, 1H), 5.16 (dd, J=21.0, 10.5Hz, 1H), 4.35-4.05 (m, 1H), 3.96-3.71 (m, 2H), 2.05 (s, 3H), 2.02-1.90(m, 2H), 1.87-1.76 (m, 1H), 1.74-1.62 (m, 1H), 1.52-1.41 (m, 2H),1.31-1.23 (m, 1H), 0.87-0.72 (m, 2H), 0.50-0.31 (m, 2H).

Example 229:(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of DMF (2 mL) was addedN-(azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 252, 100 mg, 0.21 mmol), (E)-2-cyano-3-cyclopropylprop-2-enoicacid (Intermediate 17) (58 mg, 0.42 mmol), HATU (121 mg, 0.318 mmol),and diisopropylethylamine (0.072 mL, 0.42 mmol). The mixture was stirredat rt overnight, then purified by flash column chromatography to givethe title compound as a white solid (63 mg, 50% yield). MS (ESI): masscalcd. for C₃₂H₂₆N₆O₄S, 590.7; m/z found, 591.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆ and CD₃OD): δ 8.28 (d, J=5.5 Hz, 1H), 7.41-7.34 (m, 2H),7.32-7.26 (m, 1H), 7.17-7.10 (m, 1H), 7.09-7.00 (m, 3H), 6.94-6.91 (m,1H), 6.91-6.86 (m, 1H), 5.95 (d, J=5.5 Hz, 1H), 4.75-4.65 (m, 2H),4.47-4.37 (m, 1H), 4.32-4.23 (m, 1H), 4.06-3.97 (m, 1H), 2.03 (s, 3H),1.96-1.86 (m, 1H), 1.21-1.18 (m, 2H), 0.96-0.89 (m, 2H).

Example 230:N-(1-Cyclopropylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-(azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 252, 150 mg, 0.30 mmol) and(1-ethoxycyclopropoxy)trimethylsilane (0.5 mL) in MeOH (10 mL) was addedacetic acid (1 mL), followed by sodium cyanoborohydride (93 mg, 1.5mmol). The resulting mixture was heated to reflux for 3 h, the reactionwas made basic to pH 14 with a 6 M aqueous NaOH solution, thenconcentrated to dryness, and purified by flash column chromatography toget the title compound as a yellow solid (61 mg, 40% yield). MS (ESI):mass calcd. for C₂₈H₂₅N₅O₃S, 511.6; m/z found, 512.4 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.45-8.25 (m, 1H), 7.51-7.38 (m, 2H), 7.37-7.28 (m, 1H),7.27-7.17 (m, 1H), 7.16-7.07 (m, 3H), 7.05-6.95 (m, 1H), 6.18-6.06 (m,1H), 4.70-4.52 (m, 1H), 3.89-3.69 (m, 2H), 3.45-3.37 (m, 2H), 2.16 (s,3H), 2.12-2.05 (m, 1H), 0.57-0.48 (m, 2H), 0.46-0.37 (m, 2H).

Example 231:(R,EZ)—N-(1-(2-Cyano-3-methoxyacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (EZ)-2-Cyano-3-methoxyprop-2-enoic acid

A solution of 2-cyanoacetic acid (800 mg, 9.4 mmol) in trimethoxymethane(10 mL) and acetic anhydride (2 mL) was heated at reflux under N₂overnight, and then it was concentrated to dryness. The residue wasdissolved in THF/H₂O (10 mL/10 mL) and LiOH.H₂O (790 mg, 18.8 mmol) wasadded and was stirred at rt for 2 h. The reaction was extracted withEtOAc and concentrated to dryness to give to title compound as a yellowsolid (500 mg, 42% yield).

Step B:(R,EZ)—N-(1-(2-Cyano-3-methoxyacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 200 mg, 0.40 mmol), (EZ)-2-cyano-3-methoxyprop-2-enoicacid (102 mg, 0.800 mmol), triethylamine (81 mg, 0.80 mmol), and HATU(304 mg, 0.800 mmol) in DMF (4 mL) was stirred at rt for 1 h. Water wasadded and the precipitate was collected by filtration. The residue waspurified by flash column chromatography to give the title compound as awhite solid (40 mg, 17% yield). MS (ESI): mass calcd. for C₃₂H₂₈N₆O₅S,608.7; m/z found, 609.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.38-8.26 (m,1H), 7.94-7.81 (m, 1H), 7.44-7.35 (m, 2H), 7.35-7.28 (m, 1H), 7.20-7.13(m, 1H), 7.12-7.02 (m, 3H), 7.01-6.93 (m, 1H), 6.12-6.00 (m, 1H),4.20-4.06 (m, 1H), 3.99-3.80 (m, 1H), 3.70 (s, 3H), 3.48-3.30 (m, 3H),2.16-2.05 (m, 4H), 2.01-1.91 (m, 1H), 1.83-1.68 (m, 2H).

Example 232:(R,E)-5-(*S)-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-(2-cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps C-H in Example 1, and using5-chlorobenzo[d][1,3]dioxol-4-amine in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G and Chiral resolution Method A after Step F to give the *Satropisomer. MS (ESI): mass calcd. for C₂₁H₁₈ClN₅O₄S, 471.92; m/z found,472.0 [M+H]⁺.

Step B:(R,E)-5-(*S)-(5-Chlorobenzo[d][1.3]dioxol-4-yl)-N-(1-(2-cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(110 mg, 0.23 mmol), (E)-2-cyano-3-cyclopropylprop-2-enoic acid(Intermediate 17) (32 mg, 0.23 mmol), triethylamine (94 mg, 0.93 mmol),and HATU (177 mg, 0.466 mmol) in DMF (4 mL) was stirred at roomtemperature for 3 h, then concentrated to dryness, and purified bynormal phase flash column chromatography (SiO₂) to give the titlecompound as a white solid (27 mg, 19% yield). MS (ESI): mass calcd. forC₂₈H₂₃N₆O₅S, 591.04; m/z found, 591.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆and CD₃OD): δ 8.55-8.31 (m, 1H), 7.17 (d, J=7.9 Hz, 1H), 7.07 (d, J=7.9Hz, 1H), 6.68-6.46 (m, 1H), 6.30-6.20 (m, 1H), 6.20-6.07 (m, 2H),4.18-4.03 (m, 2H), 4.03-3.96 (m, 1H), 3.26-3.07 (m, 2H), 2.11-1.97 (m,2H), 1.93-1.75 (m, 2H), 1.69-1.58 (m, 1H), 1.27-1.15 (m, 2H), 0.97-0.83(m, 2H).

Example 233:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-N-(piperidin-3-vi)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared analogous conditions described in Method1, steps D-H in Example 1, and using2-chloro-4-(2-methyl-4-tetrahydropyran-4-yloxyanilino)pyridine-3-carbonitrile(Intermediate 31) in place of2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrile in step D,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.197 mmol), (E)-2-cyano-3-cyclopropylprop-2-enoic acid(Intermediate 17) (54 mg, 0.39 mmol), HATU (97 mg, 0.26 mmol), and DIPEA(68 μL, 0.39 mmol) in DMF (5 mL) was stirred at rt for 2 h, thenpurified by flash column chromatography to yield the title compound as awhite solid (77 mg, 62% yield). MS (ESI): mass calcd. for C₃₃H₃₄N₆O₅S,626.7; m/z found, 627.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.36-8.27 (m,1H), 7.26-7.18 (m, 1H), 7.06-7.00 (m, 1H), 7.01-6.94 (m, 1H), 6.58-6.49(m, 1H), 6.07-6.00 (m, 1H), 4.69-4.59 (m, 1H), 4.27-4.10 (m, 1H),4.04-3.89 (m, 4H), 3.66-3.56 (m, 2H), 3.23-3.03 (m, 1H), 2.13 (s, 3H),2.10-1.95 (m, 5H), 1.93-1.84 (m, 1H), 1.82-1.69 (m, 3H), 1.68-1.56 (m,1H), 1.25-1.16 (m, 2H), 1.03-0.90 (m, 1H), 0.90-0.76 (m, 1H).

Example 234:(R,EZ)—N-(1-(2-Cyano-4-((2-methoxyethyl)amino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-(2-Methoxyethylamino)-2-methylpropan-1-ol

To a round bottom flask were added 2-amino-2-methylpropan-1-ol (1.0 g,11 mmol), 1-bromo-2-methoxy-ethane (1.6 g, 11 mmol), NaI (168 mg, 1.12mmol), K₂CO₃ (3.10 g, 22.4 mmol), and CH₃CN (20 mL) and the mixture wasrefluxed for 6 h. The solvent was removed under reduced pressure and theresidue was used in the next step without purification (1.22 g, 75%yield).

Step B: tert-butylN-(2-hydroxy-1,1-dimethylethyl)-N-(2-methoxyethyl)carbamate

To a round bottom flask were added2-(2-methoxyethylamino)-2-methylpropan-1-ol (1.22 g, 8.29 mmol),di-tert-butyl dicarbonate (2.17 g, 9.94 mmol), Na₂CO₃ (1.318 g, 12.43mmol), THF (20 mL), and water (20 mL) and was stirred at rt for 5 h. Themixture was extracted with EtOAc, washed with 1 M aqueous HCl, saturatedNaHCO₃ and brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness to give the title compound as a yellow liquid(462 mg, 23% yield).

Step C: tert-ButylN-(1,1-dimethyl-2-oxo-ethyl)-N-(2-methoxyethyl)carbamate

A solution of DMSO (219 mg, 2.80 mmol) in DCM (10 mL) was cooled to −78°C. and oxalyl dichloride (284 mg, 2.24 mmol) was added dropwise and themixture was stirred at −78° C. for 30 min, then tert-butylN-(2-hydroxy-1,1-dimethylethyl)-N-(2-methoxyethyl)carbamate (462 mg,1.87 mmol) dissolved in DCM (10 mL) was added dropwise and the mixturewas stirred at −78° C. for another 30 min. The reaction was quenchedwith triethylamine at −78° C. and stirred at −78° C. for 30 min. Themixture was warmed to rt and diluted with DCM, washed with saturatedNaHCO₃ and brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness to give the title compound as a colorless liquid(401 mg, 87% yield).

Step D: (R,EZ)-tert-Butyl(4-cyano-2-methyl-5-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-5-oxopent-3-en-2-yl)(2-methoxyethyl)carbamate

A solution of tert-butylN-(1,1-dimethyl-2-oxo-ethyl)-N-(2-methoxyethyl)carbamate (200 mg, 0.815mmol),(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 231 mg, 0.407 mmol), piperidine (0.3 mL), AcOH (0.1 mL),dioxane (10 mL), and 4A molecular sieves (1 g) was stirred at 100° C.for 1 h under N2. The mixture was concentrated to dryness and purifiedby flash column chromatography to give the title compound as a yellowsolid (29 mg, 9% yield).

Step E:(R,EZ)—N-(1-(2-Cyano-4-((2-methoxyethyl)amino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added (R,EZ)-tert-butyl(4-cyano-2-methyl-5-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-5-oxopent-3-en-2-yl)(2-methoxyethyl)carbamate(29 mg, 0.036 mmol), concentrated HCl (2 mL), and MeOH (2 mL) and wasstirred at rt for 1 h under N2. The mixture was concentrated to drynessand purified by flash column chromatography to give the title compoundas a white solid (11 mg, 41% yield). MS (ESI): mass calcd. forC₃₇H₃₉N₇O₅S, 693.8; m/z found, 694.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.35-8.29 (m, 1H), 7.93-7.63 (m, 1H), 7.44-7.38 (m, 2H), 7.31-7.24 (m,1H), 7.21-7.14 (m, 1H), 7.12-7.04 (m, 3H), 7.01-6.95 (m, 1H), 6.11-6.04(m, 1H), 4.60-3.95 (m, 3H), 3.89-3.75 (m, 2H), 3.70-3.56 (m, 2H),3.41-3.25 (m, 4H), 3.25-3.05 (m, 1H), 2.24-2.06 (m, 4H), 2.06-1.83 (m,2H), 1.78-1.65 (m, 1H), 1.65-1.49 (m, 6H).

Example 235:(R)-5-(2,6-Difluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions described in steps A-Gin Example 175. MS (ESI): mass calcd. for C₂₆H₂₁F₂N₅O₃S, 521.5; m/zfound, 522.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (d, J=5.56 Hz,1H), 8.16 (d, J=5.56 Hz, 1H), 7.45-7.55 (m, 2H), 7.27-7.34 (m, 1H), 7.24(d, J=7.58 Hz, 2H), 6.95 (d, J=8.08 Hz, 2H), 6.00 (d, J=5.05 Hz, 1H),4.03-4.16 (m, 1H), 3.32-3.39 (m, 1H), 3.12-3.20 (m, 1H), 2.78-2.94 (m,2H), 1.85-2.02 (m, 2H), 1.54-1.78 (m, 2H).

Example 236:N-((3S,4S)-4-Hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using tert-butyl(3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₆H₂₃N₅O₄S,501.6; m/z found, 502.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d,J=5.6 Hz, 1H), 7.46-7.33 (m, 2H), 7.31-7.23 (m, 1H), 7.19-7.13 (m, 1H),7.11-7.03 (m, 3H), 7.00-6.93 (m, 1H), 6.06 (d, J=5.5 Hz, 1H), 4.54-4.45(m, 1H), 4.40-4.30 (m, 1H), 3.79-3.68 (m, 1H), 3.60-3.51 (m, 1H),3.51-3.41 (m, 1H), 3.27-3.23 (m, 1H), 2.11 (s, 3H).

Example 237:N¹-((E)-4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)-N5-(15-oxo-19-((3aS,4R,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)glutaramide

Step A:N-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)-5-((3aS,4R,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide

To a solution of tert-butyl(15-oxo-19-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)carbamate(5.80 g, 10.6 mmol) in 5 M aqueous HCl/MeOH (30 mL) was concentratedunder vacuum at 50° C. to get the target compound as a yellow oil (5.2g, 100% yield). MS (ESI): mass calcd. for C₂₀H₃₈N₄O₅S, 446.61; m/zfound, 447.3 [M+H]⁺.

Step B: Methyl5,21-dioxo-25-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-10,13,16-trioxa-6,20-diazapentacosan-1-oate

A solution of 5-methoxy-5-oxo-pentanoic acid (1.57 g, 10.8 mmol), HATU(4.91 g, 12.9 mmol), and triethylamine (4.35 g, 43.1 mmol) in anhydrousDMF (50 mL) was stirred at room temperature for 10 minutes, thenN-(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)-5-((3aS,4R,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide(5.20 g, 10.8 mmol) was added and the mixture was stirred for 16 h. Thecrude mixture was concentrated to dryness and purified by normal phaseflash column chromatography (SiO₂) to give the title compound (3.3 g,53% yield). MS (ESI): mass calcd. for C₂₆H₄₆N₄O₈S, 574.73; m/z found,575.3 [M+H]⁺.

Step C:5,21-dioxo-25-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-10,13,16-trioxa-6,20-diazapentacosan-1-oicacid

To a solution of methyl5,21-dioxo-25-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-10,13,16-trioxa-6,20-diazapentacosan-1-oate(3.3 g, 5.7 mmol) and CaCl₂ (9.6 g, 86 mmol) in i-PrOH/H₂O (7:3, 108 mL)was added 0.5 M NaOH (14 mL) at room temperature. After 5 h, thereaction mixture was neutralized with 5 M aqueous HCl and extracted withDCM (3×100 mL), dried over anhydrous Na₂SO₄, concentrated to dryness,and purified by normal phase flash column chromatography (SiO₂) to givethe title compound as a colorless viscous foam (2.0 g, 42% yield). MS(ESI): mass calcd. for C₂₅H₄₄N₄O₈S, 560.70; m/z found, 561.3 [M+H]⁺.

Step D:N¹-((E)-4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)-N5-(15-oxo-19-((3aS,4R,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)glutaramide

A solution of5,21-dioxo-25-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-10,13,16-trioxa-6,20-diazapentacosan-1-oicacid (193 mg, 3.44 mmol), HATU (261 mg, 0.687 mmol), and triethylamine(70 mg, 0.69 mmol) in anhydrous DMF (10 mL) was stirred at roomtemperature for 10 minutes, then(R,E)-N-(1-(4-aminobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 27, 200 mg, 0.34 mmol) was added and the mixture stirred for 2h. The crude mixture was concentrated to dryness and purified by normalphase flash column chromatography (SiO₂) to give the title compound as aslight yellow solid (153 mg, 40% yield). MS (ESI): mass calcd. forC₅₆H₇₂N₁₀O₁₁S₂, 1125.4; m/z found, 1125.5 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.40-8.20 (m, 1H), 7.47-7.25 (m, 3H), 7.23-6.88 (m, 5H),6.78-6.63 (m, 1H), 6.62-6.47 (m, 1H), 6.06 (s, 1H), 4.55-4.42 (m, 1H),4.35-4.06 (m, 2H), 4.03-3.85 (m, 3H), 3.70-3.41 (m, 12H), 3.27-3.10 (m,6H), 3.05-2.84 (m, 2H), 2.75-2.60 (m, 1H), 2.34-2.00 (m, 10H), 1.95-1.81(m, 3H), 1.80-1.51 (m, 10H), 1.46-1.25 (m, 3H).

Example 238:(R,E)-N-(1-(2-Cyano-4-methyl-4-(methylamino)pent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-(tert-Butoxycarbonylamino)-2-methylpropanoic acid

To a solution of 2-amino-2-methylpropanoic acid (4.0 g, 39 mmol), NaOH(1.55 g, 38.8 mmol), water (50 mL), and THF (20 mL) was added (Boc)₂O(10.16 g, 46.55 mmol) portion wise at rt. The mixture was stirredovernight at rt, then concentrated to dryness, and extracted with EtOAc.The pH of the aqueous layer was adjusted to 3-4 with 1 M aqueous HCl,extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄,and concentrated to dryness to give the title compound as a white solid(3.21 g, 40.7% yield).

Step B: Methyl 2-(tert-butoxycarbonylamino)-2-methylpropanoate

To a round bottom flask were added2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (2.0 g, 9.8 mmol),concentrated H₂SO₄ (0.1 mL), and MeOH (20 mL) and stirred at 60° C. for5 h. The mixture was concentrated to dryness, the residue was dilutedwith EtOAc, washed with saturated NaHCO₃ and brine, dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness to give the title compoundas a white solid 1.78 g, 83.3% yield).

Step C: Methyl 2-[tert-butoxycarbonyl(methyl)amino]-2-methylpropanoate

To a solution of methyl 2-(tert-butoxycarbonylamino)-2-methylpropanoate(0.89 g, 4.10 mmol) in DMF (12 mL) was added NaH (353 mg, 14.7 mmol)portion wise at 0° C. The mixture was stirred for 5 min at thistemperature then methyl iodide (2.089 g, 14.72 mmol) was added dropwiseat 0° C. The resulting mixture was stirred at rt overnight, thenquenched with H₂O, and extracted with EtOAc. The organic phases werecombined and washed with brine, dried over anhydrous Na₂SO₄, filtered,and concentrated to dryness. The residue was purified by flash columnchromatography to give the title compound as a colorless oil (0.72 g,76% yield).

Step D: tert-Butyl N-(2-hydroxy-1,1-dimethylethyl)-N-methylcarbamate

To a suspension of LiAlH₄ (0.118 g, 3.11 mmol) in THF (15 mL) was addedmethyl 2-[tert-butoxycarbonyl(methyl)amino]-2-methylpropanoate (0.72 g,3.1 mmol) at 0° C. under N2. The mixture was stirred for 4 h at thistemperature, then it was quenched with ice/water at 0° C., extractedwith EtOAc, the organic layers washed with brine, dried over anhydrousNa₂SO₄, and concentrated to dryness to give the title compound as ayellow liquid (0.33 g, 51% yield).

Step E: tert-butyl methyl(2-methyl-1-oxopropan-2-yl)carbamate

A solution of DMSO (0.19 g, 2.4 mmol) and DCM (10 mL) was cooled to −78°C. and oxalyl dichloride (0.247 g, 1.95 mmol) was added dropwise and themixture was stirred at −78° C. for 30 min. Next, tert-butylN-(2-hydroxy-1,1-dimethylethyl)-N-methylcarbamate (0.33 g, 1.6 mmol) inDCM (5 mL) was added dropwise and the mixture was stirred at −78° C. foranother 30 min. The reaction was quenched by the addition oftriethylamine (0.328 g, 3.25 mmol) at −78° C. and stirred at −78° C. for30 min. The mixture was warmed to rt and diluted with DCM, washed withsaturated NaHCO₃ and brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness to give the title compound as a colorless liquid(0.27 g, 81% yield).

Step F: (R,E)-tert-Butyl(4-cyano-2-methyl-5-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-5-oxopent-3-en-2-yl)(methyl)carbamate

To a round bottom flask were added(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 0.253 g, 0.447 mmol), tert-butylmethyl(2-methyl-1-oxopropan-2-yl)carbamate (0.27 g, 1.3 mmol),piperidine (0.3 mL), AcOH (0.1 mL), dioxane (10 mL), and 4A molecularsieves (1 g) and was stirred at 100° C. for 1 h under N2. The mixturewas concentrated to dryness and purified by flash column chromatographyto give the title compound as a white solid (79 mg, 24% yield).

Step G:(R,E)-N-(1-(2-Cyano-4-methyl-4-(methylamino)pent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (R,E)-tert-butyl(4-cyano-2-methyl-5-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-5-oxopent-3-en-2-yl)(methyl)carbamate(79.0 mg, 0.105 mmol) in MeOH (3 mL) was added concentrated HCl (3 mL)and was stirred at rt for 30 min. The mixture was concentrated todryness, diluted with DCM, washed with saturated NaHCO₃ and brine,concentrated to dryness and purified by flash column chromatography togive the title compound as a yellow solid (44 mg, 65% yield). MS (ESI):mass calcd. for C₃₅H₃₅N₇O₄S, 649.8; m/z found, 650.3 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.35-8.30 (m, 1H), 7.92-7.61 (m, 1H), 7.42-7.35 (m, 2H),7.32-7.25 (m, 1H), 7.20-7.12 (m, 1H), 7.11-7.02 (m, 3H), 6.99-6.94 (m,1H), 6.09-6.04 (m, 1H), 4.40-3.90 (m, 3H), 3.25-2.87 (m, 5H), 2.14-2.04(m, 4H), 1.96-1.80 (m, 2H), 1.80-1.58 (m, 1H), 1.58-1.47 (m, 6H)

Example 239:(R,E)-5-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-(2-cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the same synthesis as Example 232,except that Chiral resolution Method A after Step F was used to isolatethe *R. MS (ESI): mass calcd. for C₂₈H₂₃ClN₆O₅S, 591.0; m/z found, 591.5[M+H]⁺. ¹H NMR (400 MHz, a mixture of DMSO-d₆ and CD₃OD): δ 8.52-8.34(m, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.65-6.49 (m,1H), 6.30-6.20 (m, 1H), 6.20-6.08 (m, 2H), 4.15-4.03 (m, 2H), 4.02-3.94(m, 1H), 3.26-3.10 (m, 2H), 2.12-1.98 (m, 2H), 1.94-1.72 (m, 2H),1.68-1.58 (m, 1H), 1.28-1.15 (m, 2H), 0.98-0.85 (m, 2H).

Example 240:5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methyl(sulfonyl)propanoyl)azetidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution ofN-(azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 252, 100 mg, 0.21 mmol), 3-methylsulfonylpropanoic acid (36 mg,0.23 mmol), HATU (161 mg, 0.424 mmol), and triethylamine (43 mg, 0.42mmol) in DMF (3 mL) was stirred at rt for 2 h, then purified by flashcolumn chromatography to give the title compound as a white solid (65mg, 51% yield). MS (ESI): mass calcd. for C₂₉H₂₇N₅O₆S₂, 605.7; m/zfound, 606.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 8.78 (d, J=6.6 Hz,1H), 8.31 (d, J=5.5 Hz, 1H), 7.47-7.40 (m, 2H), 7.35 (d, J=8.6 Hz, 1H),7.23-7.16 (m, 1H), 7.16-7.05 (m, 3H), 6.99-6.92 (m, 1H), 5.95 (d, J=5.5Hz, 1H), 4.77-4.62 (m, 1H), 4.52-4.40 (m, 1H), 4.23-4.10 (m, 2H),4.01-3.85 (m, 1H), 2.99 (s, 3H), 2.60-2.51 (m, 2H), 2.05 (s, 3H).

Example 241:N-((3S,4R)-4-Hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using tert-butyl(3S,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate (Intermediate 24) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₆H₂₃N₅O₄S,501.6; m/z found, 502.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.28 (d,J=5.6 Hz, 1H), 7.46-7.33 (m, 2H), 7.33-7.23 (m, 1H), 7.21-7.12 (m, 1H),7.12-7.01 (m, 3H), 6.99-6.93 (m, 1H), 6.03 (d, J=5.4 Hz, 1H), 4.61-4.56(m, 1H), 4.49-4.45 (m, 1H), 3.59-3.54 (m, 1H), 3.45-3.39 (m, 1H),3.37-3.33 (m, 1H), 3.24-3.12 (m, 1H), 2.10 (s, 3H).

Example 242:(R)-5-(2-Methyl-4-(2-(trifluoromethyl)phenoxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-Methyl-4-(2-(trifluoromethyl)phenoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using 2-(trifluoromethyl)phenol inplace of phenol in step A, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₈H₂₄F₃N₅O₃S, 567.58; m/z found,568.0 [M+H]⁺.

Step B:(R)-5-(2-Methyl-4-(2-(trifluoromethyl)phenoxy)phenyl)-N-(1-methylpiperidin-3-1)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-(2-(trifluoromethyl)phenoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(505 mg, 0.890 mmol) in DCM (10 mL) was added formaldehyde (1 mL, 37 wt.% in H₂O) and NaBH(OAc)₃ (377 mg, 1.78 mmol) and was stirred at rt for 4hours. To the mixture was added DCM (50 mL), MeOH (5 mL), water (30 mL),and aqueous NH₄OH (2 mL). The organic layer was collected, concentratedto dryness, and purified by flash column chromatography to give thetitle compound as a yellow solid (77 mg, 13% yield). MS (ESI): masscalcd. for C₂₉H₂₆F₃N₅O₃S, 581.6; m/z found, 582.4 [M+H]⁺. ¹H NMR (400MHz, DMSO-d6): δ 8.29 (d, J=5.5 Hz, 1H), 8.12-8.02 (m, 1H), 7.82-7.77(m, 1H), 7.73-7.66 (m, 1H), 7.41-7.33 (m, 2H), 7.21-7.18 (d, J=8.3 Hz,1H), 7.17-7.15 (m, 1H), 7.05-7.00 (m, 1H), 5.94 (d, J=5.5 Hz, 1H),4.01-3.94 (m, 1H), 2.94-2.85 (m, 1H), 2.77-2.68 (m, 1H), 2.27 (s, 3H),2.07 (s, 3H), 2.06-1.94 (m, 2H), 1.82-1.75 (m, 1H), 1.74-1.67 (m, 1H),1.60-1.49 (m, 1H), 1.42-1.33 (m, 1H).

Example 243:N-((3S,4S)-4-Hydroxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-((3S,4S)-4-hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 236, 100 mg, 0.2 mmol) and formaldehyde (0.5 mL, 37 wt. % inH₂O) in MeOH (5 mL) was added NaBH(OAc)₃ (127 mg, 0.597 mmol) and wasstirred at rt for 1 h, concentrated to dryness, and purified by flashcolumn chromatography to give the title compound as a white solid (68mg, 66% yield). MS (ESI): mass calcd. for C₂₇H₂₅N₅O₄S, 515.6; m/z found,516.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.26 (dd, J=5.6 Hz, 1.0, 1H),7.44-7.33 (m, 2H), 7.31-7.25 (m, 1H), 7.19-7.11 (m, 1H), 7.11-7.02 (m,3H), 7.00-6.91 (m, 1H), 6.01 (d, J=5.6 Hz, 1H), 4.35-4.25 (m, 2H),3.15-3.03 (m, 2H), 2.74-2.65 (m, 1H), 2.64-2.57 (m, 1H), 2.45 (s, 3H),2.10 (s, 3H).

Example 244:N-((3S,4S)-4-Methoxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-((3S,4S)-4-methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 245, 100 mg, 0.19 mmol) and formaldehyde (0.5 mL, 37 wt. % inH₂O) in MeOH (5 mL) was added NaBH(OAc)₃ (123 mg, 0.582 mmol) and wasstirred at rt for 1 h, concentrated to dryness, and purified by flashcolumn chromatography to give the title compound as a white solid (63mg, 60% yield). MS (ESI): mass calcd. for C₂₈H₂₇N₅O₄S, 529.6; m/z found,530.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30 (d, J=5.4 Hz, 1H),7.48-7.35 (m, 2H), 7.35-7.28 (m, 1H), 7.23-7.13 (m, 1H), 7.13-7.02 (m,3H), 7.03-6.93 (m, 1H), 6.05 (d, J=5.4 Hz, 1H), 4.53-4.39 (m, 1H),4.01-3.87 (m, 1H), 3.41 (s, 3H), 3.18-2.97 (m, 2H), 2.78-2.57 (m, 2H),2.44 (s, 3H), 2.19-2.07 (m, 3H).

Example 245:N-((3S,4S)-4-Methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using tert-butyl(3S,4S)-3-amino-4-methoxypyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₄S,515.6; m/z found, 516.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.17 (d,J=5.6 Hz, 1H), 7.39-7.32 (m, 2H), 7.25-7.19 (m, 1H), 7.16-7.09 (m, 1H),7.08-7.00 (m, 3H), 6.98-6.90 (m, 1H), 5.91 (d, J=5.6 Hz, 1H), 4.53-4.46(m, 1H), 4.04-3.96 (m, 1H), 3.49-3.44 (m, 1H), 3.43 (s, 3H), 3.41-3.37(m, 1H), 3.22-3.12 (m, 2H), 2.07 (s, 3H).

Example 246:N-(1-(3-Methoxypropanoyl)azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-(1-Acryloylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 109, 95 mg, 0.18 mmol) in MeOH (10 mL), was added NaOCH₃ (49mg, 0.91 mmol) and was stirred at 60° C. for 2 h, concentrated todryness, and the residue purified by flash column chromatography to givethe title compound as a yellow solid (33 mg, 32% yield). MS (ESI): masscalcd. for C₂₉H₂₇N₅O₅S, 557.6; m/z found, 558.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.32 (d, J=5.5, 1H), 7.44-7.35 (m, 2H), 7.32-7.26 (m, 1H),7.22-7.13 (m, 1H), 7.11-7.03 (m, 3H), 7.00-6.94 (m, 1H), 6.06 (d, J=5.5,1H), 4.79-4.74 (m, 1H), 4.60-4.52 (m, 1H), 4.36-4.29 (m, 1H), 4.29-4.19(m, 1H), 4.08-3.98 (m, 1H), 3.64 (t, J=6.0, 2H), 3.33 (s, 3H), 2.40 (t,J=6.1, 2H), 2.12 (s, 3H).

Example 247:(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-methylpent-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 100 mg, 0.2 mmol) and (E)-4-methylpent-2-enoic acid (500mg, 4.4 mmol) in anhydrous DMF (5 mL) were added HATU (228 mg, 0.600mmol) and diisopropylethylamine (130 mg, 1.0 mmol) and was stirredovernight at rt. The reaction mixture was purified by flash columnchromatography to give the title compound as a yellow solid (16 mg, 13%yield). MS (ESI): mass calcd. for C₃₃H₃₃N₅O₄S, 595.7; m/z found, 596.1[M+H]⁺. ¹H NMR (400 MHz, CDCl3): δ 9.61-9.34 (m, 1H), 8.34 (d, J=5.3 Hz,1H), 7.43-7.34 (m, 2H), 7.20-7.13 (m, 2H), 7.12-7.05 (m, 2H), 7.00 (s,1H), 6.96-6.93 (m, 1H), 6.26-6.15 (m, 1H), 6.04-5.94 (m, 1H), 4.17-4.04(m, 1H), 3.96-3.79 (m, 1H), 3.69-3.55 (m, 1H), 2.56-2.35 (m, 1H), 2.10(s, 3H), 2.08-1.83 (m, 2H), 1.81-1.59 (m, 5H), 1.161-0.96 (m, 6H).

Example 248:5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazetidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-(azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 252, 100 mg, 0.2 mmol) and formaldehyde (33 mg, 1.1 mmol, 37wt. % in H₂O) in DCM (5 mL) was added NaBH(OAc)₃ (135 mg, 0.637 mmol)and was stirred at rt overnight. The pH was adjusted to pH>7 with 2 MNaOH, then concentrated to dryness, and purified by flash columnchromatography to give the title compound as a yellow solid (41 mg, 39%yield). MS (ESI): mass calcd. for C₂₆H₂₃N₅O₃S, 485.6; m/z found, 486.1[M+H]⁺. ¹H NMR (400 MHz, a mixture of DMSO-d₆ and CD₃OD): δ 8.22 (d,J=4.9, 1H), 7.44-7.32 (m, 2H), 7.30-7.21 (m, 1H), 7.19-7.10 (m, 1H),7.10-6.98 (m, 3H), 6.97-6.84 (m, 1H), 5.89 (d, J=5.4, 1H), 4.57-4.41 (m,1H), 3.79-3.69 (m, 2H), 3.37-3.25 (m, 2H), 2.41 (s, 3H), 2.03 (s, 3H).

Example 249:(S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H (including Chiral resolution Method A after Step F to obtain the *Satropisomer) in Example 1, and using tert-butyl(3S)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To an oven dried microwave vial with a stir bar under Ar were added(S)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(103.2 mg, 0.168 mmol), sodium cyanoborohydride (25.5 mg, 0.407 mmol),and MeOH (4 mL) and was cooled to 0° C. in an ice bath. Next, aqueousformaldehyde (0.014 mL, 37 wt. % in H₂O) was added via syringe throughthe septum cap. The reaction was allowed to slowly warm to rt andstirred for an additional 30 min at rt. The crude reaction mixture wasfiltered and purified by HPLC to give the title compound (16.2 mg, 18.8%yield). MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.6; m/z found, 514.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.28 (d, J=5.6 Hz, 1H), 7.45-7.33 (m,2H), 7.29 (d, J=8.5 Hz, 1H), 7.21-6.89 (m, 5H), 6.03 (d, J=5.5 Hz, 1H),4.24-4.05 (m, 1H), 3.03-2.85 (m, 1H), 2.79-2.59 (m, 1H), 2.34 (s, 3H),2.28-2.04 (m, 5H), 1.98-1.39 (m, 4H).

Example 250:(R)-5-(4-(Cyclohexyloxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:2-Chloro-4-[4-(cyclohexoxy)-2-methylanilino]pyridine-3-carbonitrile

To a cold solution (0° C.) of2-chloro-4-(4-hydroxy-2-methylanilino)pyridine-3-carbonitrile(Intermediate 14) (1.0 g, 3.9 mmol), cyclohexanol (1.16 g, 11.5 mmol),and PPh₃ (1.5 g, 5.7 mmol) in THF (20 mL) was added DIAD (1.17 g, 5.79mmol) and was stirred at rt overnight. The mixture was concentrated todryness and the residue was purified by flash column chromatography togive the title compound as a yellow solid (400 mg, 30% yield). MS (ESI):mass calcd. for C₁₉H₂₀ClN₃O, 341.84; m/z found, 342.0 [M+H]⁺.

Step B:(R)-5-(4-(Cyclohexyloxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsD-G in Example 1, and using2-chloro-4-[4-(cyclohexoxy)-2-methylanilino]pyridine-3-carbonitrile inplace of 2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrilefor step D, and using (3R)-1-methylpiperidin-3-amine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₃₃N₅O₃S,519.7; m/z found, 520.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.48 (s, 1H),8.37-8.32 (m, 1H), 7.26-7.19 (m, 1H), 7.06-7.00 (m, 1H), 6.99-6.94 (m,1H), 6.11-6.05 (m, 1H), 4.52-4.37 (m, 1H), 4.37-4.25 (m, 1H), 3.49-3.40(m, 1H), 3.28-3.20 (m, 1H), 2.86-2.73 (m, 5H), 2.14 (s, 3H), 2.08-2.00(m, 4H), 1.89-1.81 (m, 3H), 1.72-1.50 (m, 5H), 1.46-1.37 (m, 2H).

Example 251:N-(1-Ethylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-(azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 252, 100 mg, 0.20 mmol) and acetaldehyde (0.5 mL) in MeOH (10mL) was added NaBH(OAc)₃ (209 mg, 0.985 mmol) and was stirred at rt for1 h, concentrated to dryness, and purified by flash columnchromatography to give the title compound as a white solid (50 mg, 51%yield). MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.4[M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.27 (d, J=4.9 Hz,1H), 7.49-7.38 (m, 2H), 7.36-7.27 (m, 1H), 7.23-7.15 (m, 1H), 7.15-7.03(m, 3H), 7.00-6.90 (m, 1H), 5.90 (d, J=5.3 Hz, 1H), 4.52-4.38 (m, 1H),3.68-3.60 (m, 2H), 3.11-3.20 (m, 2H), 2.61-2.50 (m, 2H), 2.05 (s, 3H),0.95-0.83 (m, 3H).

Example 252:N-(Azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl 3-aminoazetidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₅H₂₁N₅O₃S,471.5; m/z found, 472.4 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 8.95 (s,1H), 8.86 (d, J=6.5 Hz, 1H), 8.36 (d, J=5.5 Hz, 1H), 7.52-7.34 (m, 3H),7.24-7.15 (m, 1H), 7.15-7.08 (m, 3H), 7.04-6.95 (m, 1H), 6.01 (d, J=5.4Hz, 1H), 4.88-4.66 (m, 1H), 4.21-4.02 (m, 4H), 2.06 (s, 3H).

Example 253:(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butylmethyl(2-(3-(5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-2-oxoethyl)carbamate

A solution of(R)-5-(*R)(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 300, 104 mg, 0.194 mmol),2-[tert-butoxycarbonyl(methyl)amino]acetic acid (Intermediate 21) (44mg, 0.23 mmol), HATU (96 mg, 0.25 mmol), and triethylamine (0.108 mL,0.776 mmol) in DMF (3 mL) was stirred at rt overnight, then purified byflash column chromatography to give the title compound as a white solid(100 mg, 77%).

Step B:(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butylmethyl(2-(3-(5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-2-oxoethyl)carbamate(100 mg, 0.15 mmol) in HCl/MeOH (2 M, 3 mL) was stirred at rt for 4 hand concentrated to dryness. The pH was adjusted to pH>7 with saturatedNaHCO₃ and purified by flash column chromatography to give the titlecompound as a yellow solid (60 mg, 70% yield). MS (ESI): mass calcd. forC₃₀H₃₀N₆O₄S, 570.7; m/z found, 571.3 [M+H]⁺. 1H NMR (400 MHz, CD₃OD): δ8.09-7.96 (m, 1H), 7.41-7.34 (m, 2H), 7.20-7.11 (m, 2H), 7.10-7.05 (m,2H), 7.04-7.00 (m, 1H), 6.98-6.92 (m, 1H), 5.84-5.71 (m, 1H), 4.24-3.90(m, 2H), 3.86-3.77 (m, 1H), 3.66-3.55 (m, 1H), 3.53-3.42 (m, 2H),3.27-3.20 (m, 1H), 2.40-2.30 (m, 3H), 2.14-2.03 (m, 4H), 1.95-1.76 (m,2H), 1.66-1.53 (m, 1H).

Example 254:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 4-methoxyaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₄H₂₃N₅O₄S, 477.5; m/z found, 477.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.15 (d, J=16.5 Hz, 1H), 8.33 (d,J=5.5 Hz, 1H), 8.13-8.02 (m, 1H), 7.38 (d, J=8.9 Hz, 2H), 7.14 (d, J=9.0Hz, 2H), 6.90-6.72 (m, 1H), 6.12 (d, J=16.7 Hz, 1H), 6.02 (d, J=5.5 Hz,1H), 5.70 (d, J=11.0 Hz, 1H), 4.50-4.21 (m, 1H), 4.09-3.99 (m, 1H), 3.85(s, 3H), 3.79 (s, 1H), 3.17-2.94 (m, 1H), 2.82-2.60 (m, 1H), 1.96-1.94(m, 1H), 1.81-1.78 (m, 1H), 1.74-1.59 (m, 1H), 1.44 (brs, 1H).

Example 255:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-fluorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 4-fluoroaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₃H₂₀FN₅O3S, 465.5; m/z found, 466.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.27 (s, 1H), 8.33 (d, J=5.5 Hz,1H), 8.16-8.07 (m, 1H), 7.56-7.53 (m, 2H), 7.47-7.43 (m, 2H), 6.90-6.70(m, 1H), 6.11 (d, J=17.0 Hz, 1H), 6.03 (d, J=5.5 Hz, 1H), 5.69 (d,J=12.2 Hz, 1H), 4.53-4.16 (m, 1H), 4.12-3.95 (m, 1H), 3.79 (brs, 1H),3.17-2.94 (m, 1H), 2.83-2.65 (m, 1H), 1.97-1.94 (m, 1H), 1.81-1.78 (m,1H), 1.74-1.59 (m, 1H), 1.44 (brs, 1H).

Example 256:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-chlorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 4-chloroaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₃H₂₀ClN₅O₃S, 482.0; m/z found, 482.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.27 (s, 1H), 8.31 (d, J=5.5 Hz,1H), 8.15 (s, 1H), 7.68 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.5 Hz, 2H),6.89-6.71 (m, 1H), 6.11 (d, J=16.6 Hz, 1H), 6.04 (d, J=5.4 Hz, 1H), 5.69(dd, J=10.5, 2.2 Hz, 1H), 4.52-4.12 (m, 1H), 4.09-3.95 (m, 1H), 3.79 (s,1H), 3.16-2.97 (m, 1H), 2.85-2.63 (m, 1H), 2.00-1.90 (m, 1H), 1.81-1.77(m, 1H), 1.72-1.62 (m, 1H), 1.43 (s, 1H).

Example 257:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-phenyl-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using aniline in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₃H₂₁N₅O₃S, 447.5; m/z found, 448.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30-8.23 (m, 1H), 7.65-7.50 (m, 3H),7.49-7.38 (m, 2H), 6.85-6.69 (m, 1H), 6.26-6.13 (m, 1H), 6.11-6.02 (m,1H), 5.79-5.64 (m, 1H), 4.61-4.23 (m, 1H), 4.21-3.86 (m, 2H), 3.20-3.09(m, 1H), 2.95-2.80 (m, 1H), 2.10-1.97 (m, 1H), 1.91-1.80 (m, 1H),1.77-1.66 (m, 1H), 1.62-1.47 (m, 1H).

Example 258:5-(2-Methyl-4-phenoxyphenyl)-N-(2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl4-amino-2-methylpiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.6; m/z found, 514.7[M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ 8.30 (d, J=5.5 Hz, 1H),7.46-7.34 (m, 2H), 7.30 (d, J=8.6 Hz, 1H), 7.18-7.10 (m, 1H), 7.09-6.97(m, 3H), 6.96-6.86 (m, 1H), 5.97 (d, J=5.5 Hz, 1H), 4.09-3.99 (m, 1H),3.37-3.17 (m, 2H), 3.06-2.85 (m, 1H), 2.09-1.92 (m, 5H), 1.78-1.62 (m,1H), 1.60-1.50 (m, 1H), 1.23 (d, J=6.5 Hz, 3H).

Example 259:N-((3R,5R)-5-Methoxy-1-methylpiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (3R,5R)-tert-Butyl3-methoxy-5-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1 using tert-Butyl(3R,5S)-3-amino-5-methoxypiperidine-1-carboxylate (Intermediate 29) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₃H₃₅N₅O₆S,629.73; m/z found, 630.3 [M+H]⁺.

Step B:N-((3R,5R)-5-Methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(3R,5R)-tert-Butyl3-methoxy-5-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(250 mg, 0.397 mmol) was treated with concentrated HCl (2 mL) in MeOH(15 mL) at room temperature for about 2 hours. The reaction wasconcentrated to dryness to give the title compound (150 mg, 97% yield),which was carried forward to next step without any further purification.MS (ESI): mass calcd. for C₂₈H₂₇N₅O₄S, 629.73; m/z found, 630.3 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ 8.24 (d, J=5.6 Hz, 1H), 7.45-7.35 (m, 2H),7.29-7.23 (m, 1H), 7.19-7.12 (m, 1H), 7.11-7.02 (m, 3H), 7.01-6.93 (m,1H), 5.98 (d, J=5.6 Hz, 1H), 4.41-4.25 (m, 1H), 3.62-3.54 (m, 1H),3.41-3.37 (m, 3H), 3.22-3.13 (m, 1H), 3.10-3.01 (m, 1H), 2.80-2.72 (m,1H), 2.70-2.59 (m, 1H), 2.28-2.15 (m, 1H), 2.11 (s, 3H), 1.87-1.75 (m,1H).

Step C:N-((3R,5R)-5-Methoxy-1-methylpiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.

A solution ofN-((3R,5R)-5-methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(80 mg, 0.15 mmol) in DCM (5 mL) was treated with formaldehyde (1.0 mL,37 wt. % in H₂O). To the stirred reaction mixture was added NaBH(OAc)₃(65 mg, 0.31 mmol) and was stirred at room temperature for 1 h, thenconcentrated to dryness, and the residue was purified by normal phaseflash column chromatography (SiO₂) to give the title compound as yellowsolid (38 mg, 46% yield). MS (ESI): mass calcd. for C₂₉H₂₉N₅O₄S, 543.6;m/z found, 544.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.29 (d, J=5.5 Hz,1H), 7.47-7.35 (m, 2H), 7.34-7.25 (m, 1H), 7.21-7.13 (m, 1H), 7.12-7.01(m, 3H), 7.00-6.93 (m, 1H), 6.04 (d, J=5.5 Hz, 1H), 4.51-4.36 (m, 1H),3.65-3.55 (m, 1H), 3.37 (s, 3H), 2.95-2.69 (m, 2H), 2.45-2.31 (m, 4H),2.28-2.19 (m, 1H), 2.11 (s, 3H), 2.05-1.93 (m, 1H), 1.80-1.67 (m, 1H).

Example 260:(R)—N-(1-(2-chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.28 mmol), 2-chloro-3-methylbut-2-enoic acid (75mg, 0.56 mmol), HATU (138 mg, 0.364 mmol), and diisopropylethylamine (90mg, 0.70 mmol) in DMF (5 mL) was stirred at rt for 2 h. The mixture waspurified by HPLC to give the title compound as a white solid (103 mg,59.6% yield). MS (ESI): mass calcd. for C₃₂H₃₀ClN₅O₄S, 616.1; m/z found,616.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.36-8.31 (m, 1H), 7.44-7.37(m, 2H), 7.34-7.28 (m, 1H), 7.21-7.14 (m, 1H), 7.12-7.04 (m, 3H),7.01-6.95 (m, 1H), 6.11-6.06 (m, 1H), 4.52-4.23 (m, 1H), 4.05-3.71 (m,2H), 3.23-3.09 (m, 1H), 3.00-2.87 (m, 1H), 2.15-2.03 (m, 4H), 1.94-1.78(m, 7H), 1.76-1.54 (m, 2H).

Example 261:(R,Z)—N-(1-(2-Fluorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, and using analogous methods found in Example 260, using(EZ)-2-fluorobut-2-enoic acid in place of 2-chloro-3-methylbut-2-enoicacid. MS (ESI): mass calcd. for C₃₁H₂₈FN₅O₄S, 585.6; m/z found, 586.2[M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 8.29 (d, J=5.5 Hz, 1H), 8.16 (s,1H), 7.47-7.37 (m, 2H), 7.36-7.27 (m, 1H), 7.21-7.14 (m, 1H), 7.13-7.02(m, 3H), 6.98-6.90 (m, 1H), 5.92 (d, J=5.2 Hz, 1H), 5.68-5.45 (m, 1H),4.30-3.95 (m, 1H), 3.93-3.73 (m, 2H), 3.15-2.70 (m, 2H), 2.03 (s, 3H),1.96-1.88 (m, 1H), 1.84-1.71 (m, 1H), 1.69-1.60 (m, 3H), 1.59-1.49 (m,1H), 1.48-1.37 (m, 1H).

Example 262:N-(1-Methyl-5-oxopyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 4-amino-1-methylpyrrolidin-2-one in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₃N₅O₄S,513.6; m/z found, 514.7 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆/CD₃OD): δ8.28-8.21 (m, 1H), 7.41-7.32 (m, 2H), 7.28-7.23 (m, 1H), 7.15-7.09 (m,1H), 7.08-7.02 (m, 2H), 7.02-6.98 (m, 1H), 6.93-6.89 (m, 1H), 5.96-5.88(m, 1H), 4.57-4.50 (m, 1H), 3.71-3.66 (m, 1H), 3.33-3.26 (m, 1H), 2.73(s, 3H), 2.67-2.60 (m, 1H), 2.42-2.34 (m, 1H), 2.02 (s, 3H).

Example 263:(R)—N-(1-(2-Fluoro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 200 mg, 0.37 mmol), 2-fluoro-3-methylbut-2-enoic acid(Intermediate 30, 88 mg, 0.75 mmol), HATU (284 mg, 0.746 mmol), andtriethylamine (75 mg, 0.75 mmol) in DMF (4 mL) was stirred at rt for 2h, then purified by flash column chromatography to give the titlecompound as a yellow solid (135 mg, 60.3% yield). MS (ESI): mass calcd.for C₃₂H₃₀FN₅O₄S, 599.7; m/z found, 600.3 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 10.50-10.01 (br, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.15-8.00 (m,1H), 7.48-7.38 (m, 2H), 7.37-7.31 (m, 1H), 7.21-7.13 (m, 1H), 7.12-7.04(m, 3H), 7.01-6.88 (m, 1H), 5.95 (d, J=5.5 Hz, 1H), 4.45-3.98 (m, 1H),3.88-3.53 (m, 2H), 3.17-2.93 (m, 1H), 2.85-2.63 (m, 1H), 2.03 (s, 3H),1.97-1.85 (m, 1H), 1.85-1.72 (m, 1H), 1.71-1.55 (m, 7H), 1.47-1.33 (m,1H).

Example 264:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pentafluorothio)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-Methyl-4-(pentafluoro-{6}-sulfanyl)aniline

To a stirred solution ofpentafluoro-(3-methyl-4-nitrophenyl)-{6}-sulfane (1.5 g, 5.7 mmol) inethanol (50 mL) was added Fe powder (1.27 g, 22.8 mmol) followed by theslow addition of concentrated HCl (2.5 mL) at 0° C. The mixture wasstirred at rt for another 1 h, then the reaction was poured into icewater and neutralized with sodium carbonate, extracted with DCM, driedover anhydrous Na₂SO₄, filtered, and concentrated to dryness to give thetitle compound as a yellow oil (1.13 g, 85.0% yield).

Step B:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pentafluorothio)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 2-methyl-4-(pentafluoro-{6}-sulfanyl)anilinein place of 2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₃H₂₀F₅N₅O₃S₂, 573.6; m/z found,574.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.37-8.30 (m, 1H), 8.03-7.97(m, 1H), 7.93-7.86 (m, 1H), 7.65-7.57 (m, 1H), 6.69-6.54 (m, 1H),6.33-6.22 (m, 1H), 6.08-6.01 (m, 1H), 5.80-5.72 (m, 1H), 4.65-4.54 (m,1H), 4.04-3.53 (m, 4H), 2.40-1.99 (m, 5H).

Example 265:(S)-5-(2-Methyl-4-phenoxyphenl)-N-((1-methylpyrrolidin-2-yl)methyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-2-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(2S)-2-(aminomethyl)pyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(S)-5-(2-Methyl-4-phenoxyphenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(S)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-2-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(150 mg, 0.30 mmol) in MeOH (2 mL) was added formaldehyde (1 mL, 37 wt.% in H₂O) slowly and stirred for 10 min. Next, NaBH(OAc)₃ (127 mg, 0.600mmol) was added slowly and the mixture was stirred for 2 h, then NaOHwas added and the mixture was purified by flash column chromatography,then preparative TLC to give the title compound as a yellow solid (43mg, 28% yield). MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.6; m/z found,514.0 [M+H]⁺. 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J=5.5 Hz, 1H),7.45-7.34 (m, 2H), 7.20-7.14 (m, 2H), 7.12-7.07 (m, 2H), 7.02-6.99 (m,1H), 6.97-6.93 (m, 1H), 5.99 (d, J=5.5 Hz, 1H), 3.81-3.66 (m, 1H),3.43-3.28 (m, 1H), 3.28-3.12 (m, 1H), 2.73-2.53 (m, 1H), 2.43 (s, 3H),2.39-2.30 (m, 1H), 2.12 (s, 3H), 2.05-1.90 (m, 1H), 1.85-1.72 (m, 2H),1.71-1.62 (m, 1H).

Example 266:N-((3R,5S)-5-Hydroxy-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:N-((3R,5S)-5-Hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(3R,5S)-3-amino-5-hydroxypiperidine-1-carboxylate (Intermediate 2) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:N-((3R,5S)-5-Hydroxy-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-((3R,5S)-5-hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(80 mg, 0.16 mmol) and formaldehyde (0.3 mL, 37 wt. % in H₂O) in MeOH (2mL) was added NaBH(OAc)₃ (67 mg, 0.32 mmol) and was stirred at rtovernight, concentrated to dryness and purified by flash columnchromatography to give the title compound as a yellow solid (70 mg 85%yield). MS (ESI): mass calcd. for C₂₈H₂₇N₅O₄S, 529.6; m/z found, 530.2[M+H]+. ¹H NMR (400 MHz, CD₃OD): δ 8.34 (d, J=5.6 Hz, 1H), 7.44-7.36 (m,2H), 7.33-7.28 (m, 1H), 7.21-7.14 (m, 1H), 7.12-7.05 (m, 3H), 7.02-7.95(m, 1H), 6.09 (d, J=5.6 Hz, 1H), 4.41-4.27 (m, 1H), 4.10-4.39 (m, 1H),3.13-2.97 (m, 2H), 2.87-2.47 (m, 5H), 2.16-2.04 (m, 4H), 1.78-1.64 (m,1H).

Example 267:(S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G (including Chiral Resolution Method A after step F to obtain the *Ratropisomer) in Example 1, and using (3S)-tetrahydropyran-3-amine inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₄N₄O₄S,500.6; m/z found, 501.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ8.42 (d, J=5.5 Hz, 1H), 7.56-7.47 (m, 2H), 7.45-7.37 (m, 1H), 7.32-7.24(m, 1H), 7.22-7.14 (m, 3H), 7.09-7.05 (m, 1H), 6.11 (d, J=5.5 Hz, 1H),4.09-4.02 (m, 1H), 3.98-3.95 (m, 1H), 3.94-3.84 (m, 1H), 3.47-3.38 (m,1H), 3.37-3.31 (m, 1H), 2.19 (s, 3H), 2.11-2.01 (m, 1H), 1.86-1.67 (m,3H).

Example 268:N-((3R,5S)-5-Methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(3R,5S)-3-amino-5-methoxypiperidine-1-carboxylate (Intermediate 29) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₇N₅O₄S,529.6; m/z found, 530.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.38-8.31 (m,1H), 7.45-7.36 (m, 2H), 7.33-7.26 (m, 1H), 7.22-7.12 (m, 1H), 7.12-7.04(m, 3H), 7.02-6.93 (m, 1H), 6.14-6.05 (m, 1H), 4.48-4.38 (m, 1H),3.82-3.72 (m, 1H), 3.52 (s, 3H), 3.40-3.31 (m, 2H), 3.28-3.19 (m, 2H),2.27-2.17 (m, 1H), 2.16-2.08 (m, 3H), 2.07-2.00 (m, 1H).

Example 269:(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-2-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(2S)-2-(aminomethyl)pyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.1[M+H]⁺. 1H NMR (400 MHz, CDCl3): δ 8.33-8.26 (m, 1H), 7.42-7.35 (m, 2H),7.23-7.14 (m, 2H), 7.12-7.06 (m, 2H), 7.02-6.98 (m, 1H), 6.98-6.92 (m,1H), 6.54 (br, 1H), 6.03-5.90 (m, 1H), 3.59-3.51 (m, 1H), 3.47-3.39 (m,1H), 3.29-3.19 (m, 1H), 3.02-2.92 (m, 2H), 2.15-2.08 (m, 3H), 1.97-1.90(m, 1H), 1.88-1.79 (m, 1H), 1.78-1.69 (m, 1H), 1.51-1.41 (m, 1H).

Example 270:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsD-I in Example 1, and using2-chloro-4-(2-methyl-4-tetrahydropyran-4-yloxyanilino)pyridine-3-carbonitrile(Intermediate 31) in place of2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrile in step D,and using tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₉N₅O₅S,547.6; m/z found, 548.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.31-8.25 (m,1H), 7.25-7.20 (m, 1H), 7.05-7.01 (m, 1H), 6.99-6.95 (m, 1H), 6.65-6.49(m, 1H), 6.31-6.22 (m, 1H), 6.04-5.97 (m, 1H), 5.77-5.69 (m, 1H),4.67-4.55 (m, 2H), 4.01-3.90 (m, 2H), 3.87-3.76 (m, 1H), 3.76-3.65 (m,1H), 3.65-3.56 (m, 3H), 3.56-3.45 (m, 1H), 2.37-2.17 (m, 1H), 2.10 (s,3H), 2.08-2.00 (m, 3H), 1.81-1.68 (m, 2H).

Example 271:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(p-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using p-toluidine in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₄H₂₃N₅O₃S, 461.5; m/z found, 461.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.17 (d, J=16.2 Hz, 1H), 8.33 (d,J=5.5 Hz, 1H), 8.17-8.03 (m, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.3Hz, 2H), 6.89-6.72 (m, 1H), 6.12 (d, J=16.6 Hz, 1H), 6.01 (d, J=5.5 Hz,1H), 5.70 (d, J=11.2 Hz, 1H), 4.50-4.21 (m, 1H), 4.12-3.96 (m, 1H), 3.79(s, 1H), 3.16-2.94 (m, 1H), 2.77-2.63 (m, 1H), 2.42 (s, 3H), 1.96-1.93(m, 1H), 1.81-1.78 (m, 1H), 1.74-1.60 (m, 1H), 1.44 (brs, 1H).

Example 272:(R)—N-(5,5-Difluoro-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)—N-(5,5-Difluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(5R)-5-amino-3,3-difluoropiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)—N-(5,5-Difluoro-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)—N-(5,5-difluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(110 mg, 0.21 mmol) and formaldehyde (1 mL, 37 wt. % in H₂O) in MeOH (20mL) was added NaBH(OAc)₃ (218 mg, 1.03 mmol) and was stirred at rt for16 h, concentrated to dryness, and purified by flash columnchromatography to give the title compound as a yellow solid (70 mg, 62%yield). MS (ESI): mass calcd. for C₂₈H₂₅F₂N₅O₃S, 549.6; m/z found, 550.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.21 (s, 1H), 8.34 (d, J=5.5 Hz,1H), 8.05 (d, J=7.7 Hz, 1H), 7.48-7.42 (m, 2H), 7.38 (d, J=8.6 Hz, 1H),7.24-7.15 (m, 1H), 7.14-7.03 (m, 3H), 7.02-6.93 (m, 1H), 5.98 (d, J=5.5Hz, 1H), 4.26-4.08 (m, 1H), 3.03-2.93 (m, 1H), 2.92-2.80 (m, 1H),2.35-2.20 (m, 5H), 2.06 (s, 3H), 2.04-1.88 (m, 2H).

Example 273:N-(1-Isopropylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-(azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 252, 150 mg, 0.30 mmol) and acetone (1 mL) in MeOH (10 mL) wasadded NaBH(OAc)₃ (188 mg, 0.885 mmol) and was stirred at rt for 1 h,concentrated to dryness, and purified by flash column chromatography togive the title compound as a white solid (103 mg, 68.1% yield). MS(ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.6; m/z found, 514.4 [M+H]⁺. 1HNMR (400 MHz, DMSO-d6): δ 8.65-8.53 (m, 1H), 8.28 (d, J=5.5 Hz, 1H),7.48-7.38 (m, 2H), 7.36-7.28 (m, 1H), 7.24-7.15 (m, 1H), 7.14-7.03 (m,3H), 6.99-6.92 (m, 1H), 5.92 (d, J=5.4 Hz, 1H), 4.48-4.29 (m, 1H),3.63-3.55 (m, 2H), 3.13-3.06 (m, 2H), 2.46-2.39 (m, 1H), 2.04 (s, 3H),0.89 (d, J=6.2 Hz, 6H).

Example 274:(R,E)-N-(1-(4,4-Dimethylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (E)-4,4-Dimethylpent-2-enoic acid

To a solution of malonic acid (2000 mg, 19 mmol) and2,2-dimethylpropanal (827 mg, 9.60 mmol) in pyridine 20 mL was addedpiperidine (0.5 mg) and the mixture was refluxed overnight. The reactionmixture was washed with 1 M aqueous HCl, extracted with DCM, andconcentrated to dryness to give the title compound as a brown oil (1200mg), which was used in the next step without further purification.

Step B:(R,E)-N-(1-(4,4-Dimethylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 100 mg, 0.2 mmol) and (E)-4,4-dimethylpent-2-enoic acid(500 mg, 3.9 mmol) in anhydrous DMF (5 mL) were added HATU (228 mg,0.600 mmol) and diisopropylethylamine (130 mg, 1.0 mmol) and the mixturewas stirred overnight at rt. It was purified by flash columnchromatography, then TLC to give the title compound as a yellow solid(15 mg, 12% yield). MS (ESI): mass calcd. for C₃₄H₃₅N₅O₄S, 609.7; m/zfound, 610.2 [M+H]⁺. 1H NMR (400 MHz, CDCl3): δ 9.54-9.38 (m, 1H),8.42-8.28 (m, 1H), 7.42-7.36 (m, 2H), 7.21-7.14 (m, 2H), 7.12-7.06 (m,2H), 7.00 (s, 1H), 6.97-6.94 (m, 1H), 6.19-6.11 (m, 1H), 6.08-5.93 (m,1H), 4.16-4.10 (m, 1H), 3.81-3.43 (m, 4H), 2.12 (s, 3H), 1.81-1.63 (m,5H), 1.13-1.01 (m, 9H).

Example 275:5-(2-Methyl-4-phenoxyphenyl)-N-(2-morpholinoethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of 2-morpholinoethanamine (200 mg, 1.5 mmol) andtriethylamine (500 mg, 5.0 mmol) in DCM/THF (1/1) was added dropwise asolution of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride (Intermediate 32, 260 mg, 0.60 mmol) in DCM/THF(1/1). Thereaction was stirred at rt for 2 h, then it was concentrated to dryness,and purified by flash column chromatography to give the title compoundas a yellow solid (53 mg, 17% yield). MS (ESI): mass calcd. forC₂₈H₂₇N₅O₄S, 529.6; m/z found, 530.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ9.44 (br, 1H), 8.35 (d, J=5.5 Hz, 1H), 7.42-7.35 (m, 2H), 7.20-7.13 (m,2H), 7.12-7.07 (m, 2H), 7.02-6.99 (m, 1H), 6.97-6.93 (m, 1H), 6.45-6.23(m, 1H), 6.00 (d, J=5.5 Hz, 1H), 3.84-3.69 (m, 4H), 3.59-3.49 (m, 2H),2.73-2.37 (m, 6H), 2.12 (s, 3H).

Example 276:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-2-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using (R)-tert-butyl2-(aminomethyl)pyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.1[M+H]⁺. 1H NMR (400 MHz, CDCl3): δ 8.31-8.24 (m, 1H), 7.43-7.34 (m, 2H),7.25-7.20 (m, 1H), 7.20-7.14 (m, 1H), 7.11-7.07 (m, 2H), 7.00-6.98 (m,1H), 6.98-6.94 (m, 1H), 6.78 (br, 1H), 5.96-5.92 (m, 1H), 3.62-3.45 (m,2H), 3.34-3.22 (m, 1H), 3.04-2.93 (m, 2H), 2.14-2.07 (m, 3H), 1.99-1.91(m, 1H), 1.90-1.81 (m, 1H), 1.79-1.70 (m, 1H), 1.53-1.40 (m, 1H).

Example 277:(R,Z)—N-(1-(2-Chlorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.28 mmol), (Z)-2-chlorobut-2-enoic acid (67 mg,0.56 mmol), HATU (138 mg, 0.364 mmol), and diisopropylethylamine (90 mg,0.7 mmol) in DMF (5 mL) was stirred at rt for 2 h. The mixture waspurified by HPLC to give the title compound as light yellow solid (118mg, 70.0% yield). MS (ESI): mass calcd. for C₃₁H₂₈ClN₅O₄S, 602.1; m/zfound, 602.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.37-8.30 (m, 1H),7.45-7.35 (m, 2H), 7.33-7.26 (m, 1H), 7.21-7.14 (m, 1H), 7.13-7.03 (m,3H), 7.02-6.95 (m, 1H), 6.22-6.13 (m, 1H), 6.11-6.05 (m, 1H), 4.58-3.94(m, 3H), 3.23-2.92 (m, 2H), 2.17-2.02 (m, 4H), 1.94-1.81 (m, 4H),1.79-1.56 (m, 2H).

Example 278:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenoxy-2-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using 4-fluoro-1-nitro-2-(trifluoromethyl)benzenein place of 5-fluoro-2-nitrotoluene in step A, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₂₄F₃N₅O₄S, 607.6; m/z found, 608.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): □ 10.38 (s, 1H), 8.34 (d, J=5.5 Hz,1H), 8.20-8.02 (m, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.59-7.38 (m, 4H),7.35-7.14 (m, 3H), 6.90-6.65 (m, 1H), 6.20-6.00 (m, 2H), 5.66 (d, J=12.2Hz, 1H), 4.52-4.12 (m, 1H), 4.10-3.89 (m, 1H), 3.84-3.63 (m, 1H),3.16-2.88 (m, 1H), 2.83-2.55 (m, 1H), 2.05-1.85 (m, 1H), 1.85-1.51 (m,2H), 1.50-1.30 (m, 1H).

Example 279:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(m-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using m-toluidine in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₄H₂₃N₅O₃S, 461.5; m/z found, 461.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.18 (d, J=16.6 Hz, 1H), 8.33 (d,J=5.5 Hz, 1H), 8.16-8.05 (m, 1H), 7.52-7.48 (m, 1H), 7.37 (d, J=7.5 Hz,1H), 7.33-7.23 (m, 2H), 6.90-6.73 (m, 1H), 6.12 (d, J=16.6 Hz, 1H), 6.01(d, J=5.5 Hz, 1H), 5.70 (d, J=10.6 Hz, 1H), 4.51-4.21 (m, 1H), 4.09-4.00(m, 1H), 3.79 (s, 1H), 3.14-2.96 (m, 1H), 2.80-2.63 (m, 1H), 2.40 (s,3H), 1.97-1.93 (m, 1H), 1.81-1.78 (m, 1H), 1.75-1.59 (m, 1H), 1.44 (brs,1H).

Example 280:(R)-5-(4-Chloro-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 4-chloro-3-(trifluoromethyl)aniline in placeof 2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₁H₁₇ClF₃N₅O₂S, 495.9; m/z found,495.8 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=7.1 Hz, 1H), 8.23(s, 1H), 8.15 (d, J=5.5 Hz, 1H), 7.92-7.90 (m, 2H), 7.72 (dd, J=8.5, 1.9Hz, 1H), 5.97 (d, J=5.5 Hz, 1H), 4.07 (s, 1H), 3.32-3.28 (m, 1H),3.14-3.11 (m, 1H), 2.85-2.74 (m, 2H), 1.96-1.85 (m, 2H), 1.72-1.51 (m,2H).

Example 281:(R)-5-(2,3-Dimethyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(23-Dimethyl-4-phenoxyphenyl-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 1-fluoro-2,3-dimethyl-4-nitrobenzene inplace of 5-fluoro-2-nitrotoluene in step A, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)-5-(2,3-Dimethyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2,3-dimethyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(167 mg, 0.326 mmol) in DCM (10 mL) were added formaldehyde (3 mL, 37wt. % in H₂O) and NaBH(OAc)₃ (276 mg, 1.30 mmol) and was stirred at rtfor 4 h. To the mixture were added DCM (50 mL), MeOH (5 mL), and water(30 mL). The organic layer was collected, concentrated to dryness, andpurified by TLC to give the title compound as a yellow solid (75 mg, 44%yield). MS (ESI): mass calcd. for C₂₉H₂₉N₅O₃S, 527.6; m/z found, 528.2[M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 8.32-8.22 (m, 1H), 8.14-8.00 (br,1H), 7.41-7.35 (m, 2H), 7.19 (d, J=7.9 Hz, 1H), 7.13-7.07 (m, 1H),7.01-6.93 (m, 2H), 6.90 (d, J=8.7 Hz, 1H), 5.97-5.84 (m, 1H), 3.96-3.90(m, 1H), 2.85-2.79 (m, 1H), 2.69-2.62 (m, 1H), 2.20 (s, 3H), 2.18 (s,3H), 2.03 (s, 3H), 1.95-1.86 (m, 2H), 1.81-1.74 (m, 1H), 1.72-1.64 (m,1H), 1.56-1.46 (m, 1H), 1.38-1.29 (m, 1H).

Example 282:5-(2-Methyl-4-phenoxyphenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-4-oxo-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-G in Example 1, and using (1-methylpyrrolidin-3-yl)methanamine inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S,513.6; m/z found, 514.0 [M+H]+. ¹H NMR (500 MHz, CD₃OD): δ 8.46 (s, 1H),8.34 (d, J=5.5 Hz, 1H), 7.48-7.35 (m, 2H), 7.31 (dd, J=8.6, 1.3 Hz, 1H),7.22-7.13 (m, 1H), 7.13-7.02 (m, 3H), 6.98 (dd, J=8.6, 2.8 Hz, 1H), 6.09(d, J=5.5 Hz, 1H), 3.56-3.33 (m, 5H), 3.27-3.14 (m, 1H), 2.92 (s, 3H),2.88-2.74 (m, 1H), 2.33-2.20 (m, 1H), 2.12 (s, 3H), 2.00-1.86 (m, 1H).

Example 283:(R)-5-(4-(2-Isopropoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(2-Isopropoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 2-isopropoxyphenol in place of phenol instep A, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)-5-(4-(2-Isopropoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(2-isopropoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(187 mg, 0.315 mmol) and formaldehyde (1 mL, 37 wt. % in H₂O) in MeOH(10 mL) was added NaBH(OAc)₃ (200 mg, 0.95 mmol) and was stirred at rtfor 1 h, concentrated to dryness, and purified by flash columnchromatography to give the title compound as a white solid (122 mg,67.3% yield). MS (ESI): mass calcd. for C₃₁H₃₃N₅O₄S, 571.7; m/z found,572.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.30 (d, J=5.5 Hz, 1H), 8.15(s, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.32-7.23 (m, 1H), 7.22-7.07 (m, 3H),7.03-6.88 (m, 2H), 6.86-6.75 (m, 1H), 5.86 (d, J=5.5 Hz, 1H), 4.62-4.51(m, 1H), 4.00-3.93 (m, 1H), 2.95-2.84 (m, 1H), 2.77-2.64 (m, 1H), 2.27(s, 3H), 2.02 (s, 5H), 1.83-1.66 (m, 2H), 1.57-1.48 (m, 1H), 1.48-1.33(m, 1H), 1.15 (d, J=6.0 Hz, 6H).

Example 284:(R)-5-(4-Cyclobutoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-cyclobutoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 605) (150 mg, 0.31 mmol) and formaldehyde (0.5 mL, 37 wt. % inH₂O) in DCM (2 mL) was added NaBH(OAc)₃ (200 mg, 0.95 mmol) and wasstirred at rt for overnight. The reaction was quenched by the additionof water (10 mL), extracted with DCM, dried over anhydrous Na₂SO₄,filtered, concentrated to dryness, and purified by flash columnchromatography to give the title compound as a yellow solid (65 mg, 42%yield). MS (ESI): mass calcd. for C₂₆H₂₉N₅O₃S, 491.6; m/z found, 492.0[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32-8.27 (m, 1H), 7.24-7.17 (m, 1H),6.92-6.86 (m, 1H), 6.86-6.78 (m, 1H), 6.02-5.94 (m, 1H), 4.80-4.66 (m,1H), 4.33-4.19 (m, 1H), 3.49-3.36 (m, 1H), 3.27-3.17 (m, 1H), 2.84-2.69(m, 5H), 2.56-2.40 (m, 2H), 2.19-2.06 (m, 5H), 2.06-1.95 (m, 2H),1.92-1.58 (m, 4H).

Example 285:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-2-yl)methyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(2R)-2-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-2-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(150 mg, 0.3 mmol) in MeOH (2 mL) was added formaldehyde (1 mL, 37 wt. %in H₂O) slowly and was stirred for 10 min, then NaBH(OAc)₃ (127 mg, 0.6mmol) was added slowly and the mixture was stirred for 2 h, then NaOH (2mL) was added and the mixture was purified by flash columnchromatography, then by preparative TLC to give the title compound as ayellow solid (75 mg, 47% yield). MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S,513.6; m/z found, 514.0 [M+H]+. ¹H NMR (400 MHz, CDCl₃): δ 9.05-8.96 (m,1H), 8.61-8.56 (m, 1H), 8.34 (d, J=5.5 Hz, 1H), 7.41-7.36 (m, 2H),7.19-7.14 (m, 2H), 7.11-7.07 (m, 2H), 7.02-6.98 (m, 1H), 6.96-6.92 (m,1H), 5.97 (d, J=5.5 Hz, 1H), 3.86-3.79 (m, 1H), 3.78-3.67 (m, 2H),3.51-3.39 (m, 1H), 2.87-2.74 (m, 4H), 2.29-2.20 (m, 1H), 2.12 (s, 3H),2.10-2.02 (m, 2H), 1.95-1.83 (m, 1H).

Example 286:(R)-5-(4-(3,5-Difluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(3,5-Difluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 3,5-difluorophenol and4-fluoro-2-methyl-1-nitrobenzene in place of 5-fluoro-2-nitrotoluene andphenol in step A, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)-5-(4-(3,5-Difluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(3,5-difluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(120 mg, 0.22 mmol) in DCM (1 mL) were added formaldehyde (0.5 mL, 37wt. % in H₂O) and NaBH(OAc)₃ (140 mg, 0.66 mmol) and was stirred at rtfor 20 min. The reaction was quenched by the addition of water (10 mL),extracted with DCM, dried over anhydrous Na₂SO₄, filtered, concentratedto dryness, and purified by flash column chromatography to give thetitle compound as a white solid (75 mg, 60% yield). MS (ESI): masscalcd. for C₂₈H₂₅F₂N₅O₃S, 549.6; m/z found, 550.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.29 (d, J=5.5 Hz, 1H), 7.42-7.33 (m, 1H), 7.21-7.14 (m,1H), 7.12-7.02 (m, 1H), 6.74-6.61 (m, 3H), 6.05 (d, J=5.5 Hz, 1H),4.22-4.09 (m, 1H), 3.02-2.85 (m, 1H), 2.77-2.64 (m, 1H), 2.34 (s, 3H),2.27-2.17 (m, 2H), 2.16 (s, 3H), 1.94-1.77 (m, 2H), 1.75-1.62 (m, 1H),1.56-1.42 (m, 1H).

Example 287:(R)—N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-G (including Chiral Resolution Method A after step F to obtain the *Ratropisomer) in Example 1, and using1-[(3R)-3-amino-1-piperidyl]-2-(dimethylamino)ethanone (Intermediate 43)in place of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₁H₃₂N₆O₄S,584.7; m/z found, 585.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33-8.21 (m,1H), 7.48-7.34 (m, 2H), 7.31-7.24 (m, 1H), 7.20-7.14 (m, 1H), 7.12-7.04(m, 3H), 7.02-6.92 (m, 1H), 6.05-5.98 (m, 1H), 4.37-3.79 (m, 3H),3.63-3.40 (m, 2H), 3.26-2.96 (m, 2H), 2.50-2.37 (m, 6H), 2.12 (s, 3H),2.02-1.98 (m, 1H), 1.88-1.68 (m, 2H), 1.68-1.51 (m, 1H).

Example 288:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 3-(trifluoromethyl)aniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₄H₂₀F₃N₅O3S, 515.5; m/z found, 516.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.25 (s, 1H), 8.34 (d, J=5.4 Hz,1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.94 (d, J=7.4 Hz, 1H), 7.90-7.81 (m,2H), 6.90-6.72 (m, 1H), 6.12 (d, J=16.6 Hz, 1H), 6.03 (d, J=5.5 Hz, 1H),5.69 (d, J=12.4 Hz, 1H), 4.53-4.15 (m, 1H), 4.12-3.95 (m, 1H), 3.80(brs, 1H), 3.18-2.94 (m, 1H), 2.85-2.61 (m, 1H), 1.97-1.94 (m, 1H),1.81-1.79 (m, 1H), 1.75-1.59 (m, 1H), 1.44 (brs, 1H).

Example 289:(S)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral Resolution Method A after step F to obtain the *Ratropisomer) in Example 1, and using tert-butyl(3S)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₄S, 553.6; m/z found, 554.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.27 (dd, J=7.7, 5.3 Hz, 1H),7.46-7.35 (m, 2H), 7.29 (dd, J=8.7, 2.6 Hz, 1H), 7.23-6.93 (m, 5H),6.86-6.73 (m, 1H), 6.25-6.12 (m, 1H), 6.08-5.95 (m, 1H), 5.82-5.66 (m,1H), 4.69-4.46 (m, 1H), 4.39-4.09 (m, 1H), 4.06-3.83 (m, 1H), 3.27-3.11(m, 1H), 2.98-2.85 (m, 1H), 2.22-2.01 (m, 4H), 1.97-1.42 (m, 3H).

Example 290:(R)-5-(2-Methyl-4-(p-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-Methyl-4-(p-tolyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using p-cresol in place of phenol in step A, andusing tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)-5-(2-Methyl-4-(p-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-(p-tolyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(92 mg, 0.18 mmol) in DCM (5 mL) were added formaldehyde (0.5 mL, 37 wt.% in H₂O) and NaBH(OAc)₃ (76 mg, 0.36 mmol) and was stirred at rt for 4hours. To the mixture was added DCM (50 mL), MeOH (5 mL), and water (30mL). The organic layer was collected, concentrated to dryness, andpurified by flash column chromatography to give the title compound as ayellow solid (54 mg, 56% yield). MS (ESI): mass calcd. for C₂₉H₂₉N₅O₃S,527.6; m/z found, 528.0 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 8.26 (d,J=5.5 Hz, 1H), 8.09-7.97 (m, 1H), 7.32-7.27 (m, 1H), 7.23-7.19 (m, 2H),7.01-6.97 (m, 3H), 6.92-6.87 (m, 1H), 5.88 (d, J=5.5 Hz, 1H), 3.95-3.88(m, 1H), 2.85-2.78 (m, 1H), 2.70-2.61 (m, 1H), 2.28 (s, 3H), 2.19 (s,3H), 2.01 (s, 3H), 1.94-1.84 (m, 2H), 1.78-1.72 (m, 1H), 1.70-1.63 (m,1H), 1.53-1.44 (m, 1H), 1.36-1.27 (m, 1H).

Example 291:(S)-5-(2-Methyl-4-phenoxyphenyl)-N-(2-(3-methylmorpholino)ethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of 2-[(3S)-3-methylmorpholin-4-yl]ethanamine (260 mg, 1.8mmol) in DCM/THF (1/1) and triethylamine (312 mg, 2.4 mmol) was added5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride (Intermediate 32, 261 mg, 0.600 mmol) in DCM/THF(1/1) dropwise,and it was stirred for 2 h at rt. The reaction mixture was concentratedto dryness and purified by flash column chromatography, then preparativeTLC to give the title compound as a yellow solid (15 mg, 4.5% yield). MS(ESI): mass calcd. for C₂₉H₂₉N₅O₄S, 543.6; m/z found, 544.0 [M+H]⁺. 1HNMR (400 MHz, CDCl3): δ 8.33 (d, J=5.1 Hz, 1H), 7.44-7.34 (m, 2H),7.21-7.12 (m, 2H), 7.12-7.05 (m, 2H), 7.01-6.97 (m, 1H), 6.97-6.90 (m,1H), 6.39-6.31 (m, 1H), 5.99 (d, J=5.1 Hz, 1H), 3.85-3.78 (m, 1H),3.74-3.63 (m, 2H), 3.61-3.54 (m, 1H), 3.42-3.34 (m, 1H), 3.33-3.26 (m,1H), 3.02-2.91 (m, 1H), 2.85-2.76 (m, 1H), 2.59-2.48 (m, 1H), 2.43-2.31(m, 2H), 2.11 (s, 3H), 1.05-0.96 (m, 3H).

Example 292:(R,E)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R,E)-tert-Butylmethyl(4-(3-(5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate

A solution of(R)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 300, 80 mg, 0.16 mmol),(E)-4-[tert-butoxycarbonyl(methyl)amino]but-2-enoic acid (Intermediate10, 52 mg, 0.24 mmol), HATU (79 mg, 0.21 mmol), anddiisopropylethylamine (52 mg, 0.40 mmol) in DMF (3 mL) was stirred at rtfor 2 h. The mixture was purified by HPLC, then by flash columnchromatography to give the title compound as a white solid (59 mg, 53%yield). MS (ESI): mass calcd. for C₃₇H₄₀N₆O₆S, 696.82; m/z found, 697.3[M+H]⁺.

Step B:(R,E)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added (R,E)-tert-butylmethyl(4-(3-(5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate(59 mg, 0.085 mmol), concentrated HCl (3 mL), and MeOH (3 mL) and wasstirred at rt for 1 h. The mixture was concentrated to dryness and waspurified by flash column chromatography to give the title compound as awhite solid (27 mg, 49% yield). MS (ESI): mass calcd. for C₃₂H₃₂N₆O₄S,596.7; m/z found, 597.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.47 (s, 1H),8.37-8.30 (m, 1H), 7.44-7.37 (m, 2H), 7.34-7.27 (m, 1H), 7.21-7.14 (m,1H), 7.13-7.04 (m, 3H), 7.01-6.95 (m, 1H), 6.92-6.82 (m, 1H), 6.74-6.60(m, 1H), 6.12-6.05 (m, 1H), 4.54-3.91 (m, 3H), 3.84-3.75 (m, 2H),3.25-3.08 (m, 1H), 3.00-2.81 (m, 1H), 2.71 (s, 3H), 2.18-2.02 (m, 4H),1.94-1.83 (m, 1H), 1.82-1.67 (m, 1H), 1.66-1.53 (m, 1H).

Example 293:(R)-5-(2-Methyl-4-(pyridin-3-yloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-Methyl-4-(pyridin-3-yloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 2-methyl-4-(3-pyridyloxy)aniline in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₆H₂₄N₆O₃S, 500.57; m/z found, 501.1[M+H]⁺.

Step B:(R)-5-(2-Methyl-4-(pyridin-3-yloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-(pyridin-3-yloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.2 mmol) and formaldehyde (0.3 mL, 37 wt. % in H₂O) in MeOH (5mL) was added NaBH(OAc)₃ (127 mg, 0.6 mmol) and was stirred at rt for 1h, concentrated to dryness, and purified by flash column chromatographyto give the title compound as a tan solid (59 mg, 56% yield). MS (ESI):mass calcd. for C₂₇H₂₆N₆O₃S, 514.6; m/z found, 515.0 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.43-8.38 (m, 1H), 8.38-8.32 (m, 1H), 8.32-8.26 (m, 1H),7.63-7.54 (m, 1H), 7.53-7.43 (m, 1H), 7.41-7.33 (m, 1H), 7.21-7.12 (m,1H), 7.11-7.03 (m, 1H), 6.13-597 (m, 1H), 4.21-4.10 (m, 1H), 3.03-2.88(m, 1H), 2.82-2.65 (m, 1H), 2.36 (s, 3H), 2.29-2.18 (m, 2H), 2.15 (s,3H), 1.94-1.77 (m, 2H), 1.75-1.63 (m, 1H), 1.57-1.44 (m, 1H).

Example 294:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-chlorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 3-chloroaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₃H₂₀ClN₅O₃S, 481.1; m/z found, 482.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.26 (d, J=14.5 Hz, 1H), 8.35 (d,J=5.5 Hz, 1H), 8.14-8.09 (m, 1H), 7.68 (s, 1H), 7.66-7.65 (m, 2H),7.54-7.45 (m, 1H), 6.90-6.71 (m, 1H), 6.12 (d, J=17.1 Hz, 1H), 6.08 (d,J=5.5 Hz, 1H), 5.70 (d, J=11.1 Hz, 1H), 4.50-4.48 (m, 1H), 3.99 (s, 1H),3.81 (s, 1H), 3.16-2.95 (m, 1H), 2.81-2.63 (m, 1H), 1.98-1.94 (m, 1H),1.86-1.59 (m, 2H), 1.44 (s, 1H).

Example 295:(R)-5-(4-(4-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(4-Fluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 4-fluorophenol in place of phenol in step A,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)-5-(4-(4-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(4-fluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(84 mg, 0.16 mmol) in DCM (5 mL) were added formaldehyde (0.5 mL, 37 wt.% in H₂O) and NaBH(OAc)₃ (69 mg, 0.33 mmol) and was stirred at rt for 4hours. To the mixture was added DCM (50 mL), MeOH (5 mL), and water (30mL). The organic layer was collected, concentrated to dryness, andpurified by flash column chromatography to give the title compound as ayellow solid (52 mg, 60% yield). MS (ESI): mass calcd. for C₂₈H₂₆FN₅O₃S,531.6; m/z found, 532.0 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 8.26 (d,J=5.4 Hz, 1H), 8.04 (br, 1H), 7.33-7.29 (m, 1H), 7.28-7.22 (m, 2H),7.18-7.13 (m, 2H), 7.05-7.01 (m, 1H), 6.94-6.90 (m, 1H), 5.88 (d, J=5.5Hz, 1H), 3.95-3.87 (m, 1H), 2.86-2.78 (m, 1H), 2.70-2.62 (m, 1H), 2.19(s, 3H), 2.02 (s, 3H), 1.94-1.84 (m, 2H), 1.79-1.72 (m, 1H), 1.70-1.63(m, 1H), 1.53-1.43 (m, 1H), 1.36-1.26 (m, 1H).

Example 296:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(2-(3-methylmorpholino)ethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of 2-[(3R)-3-methylmorpholin-4-yl]ethanamine (260 mg, 1.8mmol) in DMF (5 mL) and triethylamine (312 mg, 2.40 mmol) was added5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride (Intermediate 32, 261 mg, 0.600 mmol) in DCM/THF(1/1) was addeddropwise. The reaction was stirred for 2 h at rt, concentrated todryness, and purified by flash column chromatography, then preparativeTLC to give the title compound as a yellow solid (30 mg, 9% yield). MS(ESI): mass calcd. for C₂₉H₂₉N₅O₄S, 543.6; m/z found, 544.0 [M+H]⁺. 1HNMR (400 MHz, CDCl3): δ 8.33 (d, J=5.5 Hz, 1H), 7.42-7.34 (m, 2H),7.21-7.13 (m, 2H), 7.12-7.06 (m, 2H), 7.01-6.98 (m, 1H), 6.97-6.91 (m,1H), 6.38-6.31 (m, 1H), 5.99 (d, J=5.5 Hz, 1H), 3.84-3.77 (m, 1H),3.75-3.70 (m, 1H), 3.69-3.62 (m, 1H), 3.62-3.54 (m, 1H), 3.42-3.32 (m,1H), 3.32-3.26 (m, 1H), 3.02-2.90 (m, 1H), 2.84-2.76 (m, 1H), 2.59-2.47(m, 1H), 2.43-2.32 (m, 2H), 2.12 (s, 3H), 1.04-0.97 (m, 3H).

Example 297:(R)-5-(4-(Cyclopentyloxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(cyclopentyloxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 919, 80 mg, 0.16 mmol) in DCM (2 mL) were added formaldehyde(0.5 mL, 37 wt. % in H₂O) and NaBH(OAc)₃ (200 mg) and was reacted at rtovernight. The reaction was quenched with H₂O (10 mL), extracted withDCM, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness.The residue was purified by flash column chromatography to give thetitle compound as a yellow solid (48 mg, 58% yield). MS (ESI): masscalcd. for C₂₇H₃₁N₅O₃S, 505.6; m/z found, 506.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.35-8.27 (m, 1H), 7.24-7.15 (m, 1H), 6.97-6.91 (m, 1H),6.90-6.86 (m, 1H), 6.08-6.00 (m, 1H), 4.89-4.85 (m, 1H), 4.39-4.18 (m,1H), 3.65-3.50 (m, 1H), 3.48-3.33 (m, 1H), 3.04-2.90 (m, 2H), 2.88-2.86(m, 3H), 2.09 (s, 3H), 2.08-1.99 (m, 2H), 199-1.91 (m, 2H), 1.89-1.83(m, 2H), 1.82-1.69 (m, 4H), 1.68-1.59 (m, 2H).

Example 298:5-(2-Methyl-4-phenoxyphenyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-oxo-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 2-(1-methylpyrrolidin-2-yl)ethanamine inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₉H₂₉N₅O₃S,527.6; m/z found, 528.0 [M+H]⁺. 1H NMR (500 MHz, DMSO-d6) δ 8.54-8.35(m, 1H), 8.35-8.17 (m, 1H), 7.56-6.88 (m, 9H), 6.01-5.79 (m, 1H),3.13-2.96 (m, 1H), 2.35-1.50 (m, 16H).

Example 299:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-Methoxy-2-methylphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsB-I in Example 1, and using 4-methoxy-2-methyl-1-nitrobenzene in placeof 2-methyl-1-nitro-4-phenoxybenzene in step B, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of triethylamine (0.105 mL, 0.756 mmol) in THF (5 mL) wasadded(R)-5-(4-methoxy-2-methylphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(160 mg, 0.38 mmol). After stirring at rt for 5 min, acrylic acid (30mg, 0.42 mmol), EDCI (87 mg, 0.45 mmol), and HOBt (61 mg, 0.45 mmol)were added. The reaction mixture was stirred at rt for 30 min,concentrated to dryness, and the residue was purified by flash columnchromatography to give the title compound as a yellow solid (27 mg, 14%yield). MS (ESI): mass calcd. for C₂₄H₂₃N₅O₄S, 477.5; m/z found, 478.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ 8.24 (d, J=5.5, 1H),7.21-7.11 (m, 1H), 6.98-6.91 (m, 1H), 6.91-6.84 (m, 1H), 6.60-6.43 (m,1H), 6.20-6.11 (m, 1H), 5.90 (d, J=5.5, 1H), 5.69-5.62 (m, 1H),4.60-4.45 (m, 6.2, 1H), 3.93-3.83 (m, 1H), 3.77 (s, 3H), 3.75-3.67 (m,1H), 3.65-3.56 (m, 1H), 3.45-3.39 (m, 1H), 2.26-2.08 (m, 1H), 2.08-1.91(m, 4H).

Example 300:(R)-5-(*R)-(2-Methyl-4-phenoxyphenl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsG-H in Example 1, and using5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 63) and tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.21 (d, J=5.5 Hz, 1H), 7.44-7.35 (m,2H), 7.28-7.21 (m, 1H), 7.19-7.13 (m, 1H), 7.13-7.03 (m, 3H), 7.00-6.92(m, 1H), 5.95 (d, J=5.6 Hz, 1H), 4.24-4.07 (m, 1H), 3.28-3.23 (m, 1H),3.13-3.03 (m, 1H), 2.91-2.73 (m, 2H), 2.11 (s, 3H), 2.07-1.98 (m, 1H),1.96-1.88 (m, 1H), 1.80-1.64 (m, 2H).

Example 301:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-fluorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 2-fluoroaniline in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₂H₁₈FN₅O₃S, 451.5; m/z found, 452.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.38 (s, 1H), 8.50-8.34 (m, 1H),8.32 (d, J=5.4 Hz, 1H), 7.70-7.56 (m, 2H), 7.55-7.35 (m, 2H), 6.69-6.42(m, 1H), 6.20-6.08 (m, 1H), 6.05 (d, J=5.2 Hz, 1H), 5.72-5.57 (m, 1H),4.59-4.33 (m, 1H), 3.88-3.59 (m, 2H), 3.57-3.39 (m, 2H), 2.23-1.91 (m,2H).

Example 302:(R)-5-(4-(2,4-Difluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(2,4-difluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 2,4-difluorophenol in place of phenol instep A, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)-5-(4-(2,4-Difluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(2,4-difluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(210 mg, 0.39 mmol) and formaldehyde (0.5 mL, 37 wt. % in H₂O) in MeOH(10 mL) was added NaBH(OAc)₃ (249 mg, 1.18 mmol) and was stirred at rtfor 1 h, concentrated to dryness, and purified by flash columnchromatography to give the title compound as a white solid 190 mg, 87%yield). MS (ESI): mass calcd. for C₂₈H₂₅F₂N₅O₃S, 549.6; m/z found, 549.9[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33-8.25 (m, 1H), 7.37-7.21 (m, 2H),7.21-7.10 (m, 1H), 7.08-6.97 (m, 2H), 6.96-6.87 (m, 1H), 6.10-5.96 (m,1H), 4.28-4.15 (m, 1H), 3.28-3.17 (m, 1H), 3.07-2.94 (m, 1H), 2.66-2.48(m, 5H), 2.11 (s, 3H), 2.00-1.88 (m, 2H), 1.83-1.70 (m, 1H), 1.65-1.52(m, 1H).

Example 303:(R)-5-(5-Fluoro-2-methyl-4-phenoxyphenl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(5-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 1-bromo-2-fluoro-5-methyl-4-nitrobenzene(Intermediate 45) in place of 5-fluoro-2-nitrotoluene in step A, andusing tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₄FN₅O₃S,517.58; m/z found, 518.0 [M+H]⁺.

Step B:(R)-5-(5-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(5-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(115 mg, 0.222 mmol) in DCM (5 mL) was added formaldehyde (0.5 mL, 37wt. % in H₂O) and NaBH(OAc)₃ (94 mg, 0.44 mmol) and was stirred at rtfor 4 hours. To the mixture was added DCM (50 mL), MeOH (5 mL), andwater (30 mL). The organic layer was collected, concentrated to dryness,and purified by flash column chromatography to give the title compoundas a yellow solid (68 mg, 57% yield). MS (ESI): mass calcd. forC₂₈H₂₆FN₅O₃S, 531.6; m/z found, 532.0 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6):δ 8.34-8.22 (m, 1H), 8.15 (br, 1H), 7.55-7.45 (m, 1H), 7.44-7.35 (m,2H), 7.24-7.18 (m, 1H), 7.18-7.12 (m, 1H), 7.12-7.01 (m, 2H), 6.06-5.93(m, 1H), 3.98-3.85 (m, 1H), 2.87-2.78 (m, 1H), 2.72-2.59 (m, 1H), 2.20(s, 3H), 1.99 (s, 3H), 1.95-1.87 (m, 2H), 1.80-1.72 (m, 1H), 1.70-1.64(m, 1H), 1.55-1.45 (m, 1H), 1.36-1.26 (m, 1H).

Example 304:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2,4-dimethylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2,4-dimethylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-G in Example 1, and using 2,4-dimethylaniline in place of2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-Aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate 5) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₄H₂₃N₅O₃S,461.5; m/z found, 462.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.29-10.12(m, 1H), 8.48-8.34 (m, 1H), 8.31-8.19 (m, 1H), 7.28-7.25 (m, 1H),7.23-7.13 (m, 2H), 6.66-6.49 (m, 1H), 6.19-6.07 (m, 1H), 5.87-5.77 (m,1H), 5.71-5.60 (m, 1H), 4.57-4.35 (m, 1H), 3.90-3.40 (m, 4H), 2.34 (s,3H), 2.20-2.08 (m, 1H), 2.03 (s, 3H), 2.00-1.89 (m, 1H).

Example 305:(R)-5-(5-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 1-bromo-2-fluoro-5-methyl-4-nitrobenzene(Intermediate 45) in place of 5-fluoro-2-nitrotoluene in step A, andusing (3R)-tetrahydropyran-3-amine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₃FN₄O₄S, 518.6; m/z found, 519.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.25 (br, 1H), 8.36-8.29 (m, 1H),8.01 (br, 1H), 7.59-7.52 (m, 1H), 7.44-7.40 (m, 2H), 7.23 (d, J=8.8 Hz,1H), 7.19-7.14 (m, 1H), 7.11-7.07 (m, 2H), 6.13-6.03 (m, 1H), 3.93-3.85(m, 1H), 3.82-3.73 (m, 2H), 3.27-3.24 (m, 1H), 3.21-3.15 (m, 1H), 2.02(s, 3H), 1.93-1.88 (m, 1H), 1.71-1.55 (m, 3H).

Example 306:(R)-5-(2-Methyl-4-(pyridin-2-yloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-Methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using pyridin-2-ol in place of phenol in step A,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)-5-(2-Methyl-4-(pyridin-2-yloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(150 mg, 0.30 mmol) in MeOH (5 mL) was added formaldehyde (1 mL, 37 wt.% in H₂O) slowly and stirred for 10 min, then NaBH(OAc)₃ (127 mg, 0.600mmol) was added slowly and the mixture was stirred for 2 h, then NaOH (2mL) was added and the mixture was purified by flash columnchromatography, then preparative TLC to give the title compound as ayellow solid (81 mg, 52% yield). MS (ESI): mass calcd. for C₂₇H₂₆N₆O₃S,514.6; m/z found, 515.1 [M+H]⁺. 1H NMR (400 MHz, CDCl3): δ 8.35 (d,J=5.4 Hz, 1H), 8.29-8.18 (m, 1H), 7.80-7.67 (m, 1H), 7.25-7.21 (m, 1H),7.18 (s, 1H), 7.16-7.11 (m, 1H), 7.09-7.03 (m, 1H), 7.00-6.94 (m, 1H),6.36-6.15 (m, 1H), 6.07 (d, J=5.4 Hz, 1H), 4.31-4.17 (m, 1H), 2.65-2.37(m, 3H), 2.28 (s, 3H), 2.22-2.10 (m, 4H), 1.81-1.58 (m, 4H).

Example 307:(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G (including Chiral Resolution Method A after step F to obtain the *Ratropisomer) in Example 1, and using (3R)-tetrahydropyran-3-amine inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₄N₄O₄S,500.6; m/z found, 501.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ8.42 (d, J=5.5 Hz, 1H), 7.56-7.47 (m, 2H), 7.44-7.34 (m, 1H), 7.32-7.25(m, 1H), 7.23-7.13 (m, 3H), 7.07-7.01 (m, 1H), 6.11 (d, J=5.5 Hz, 1H),4.12-4.00 (m, 1H), 3.99-3.83 (m, 2H), 3.48-3.37 (m, 1H), 3.36-3.31 (m,1H), 2.18 (s, 3H), 2.10-1.97 (m, 1H), 1.86-1.66 (m, 3H).

Example 308:(S)-5-(5-Fluoro-2-methyl-4-phenoxyphenl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 1-bromo-2-fluoro-5-methyl-4-nitrobenzene(Intermediate 45) in place of 5-fluoro-2-nitrotoluene in step A, andusing (3S)-tetrahydropyran-3-amine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₃FN₄O₄S, 518.6; m/z found, 519.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.25 (br, 1H), 8.34 (d, J=5.4 Hz,1H), 7.97 (br, 1H), 7.60-7.52 (m, 1H), 7.44-7.39 (m, 2H), 7.23 (d, J=8.8Hz, 1H), 7.19-7.14 (m, 1H), 7.11-7.07 (m, 2H), 6.09 (d, J=5.5 Hz, 1H),3.94-3.85 (m, 1H), 3.82-3.74 (m, 2H), 3.27-3.23 (m, 1H), 3.21-3.15 (m,1H), 2.02 (s, 3H), 1.94-1.88 (m, 1H), 1.70-1.54 (m, 3H).

Example 309:(S)—N-(1-Benzyl-2-oxoazepan-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using (3S)-3-amino-1-benzyl-azepan-2-one in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₅H₃₁N₅O₄S,617.7; m/z found, 618.0 [M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.31 (s,1H), 7.51-7.37 (m, 2H), 7.37-7.26 (m, 6H), 7.23-7.14 (m, 1H), 7.14-7.03(m, 3H), 7.03-6.95 (m, 1H), 6.09-5.99 (m, 1H), 4.75-4.70 (m, 1H),4.62-4.57 (m, 1H), 3.77-3.54 (m, 1H), 3.03-2.83 (m, 2H), 2.13 (s, 3H),1.99-1.87 (m, 2H), 1.79-1.65 (m, 3H), 1.36-1.18 (m, 1H).

Example 310:(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-2-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using (S)-2-aminomethyl-1-N-Boc-piperidine inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S,513.62; m/z found, 514.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.45-8.22(m, 1H), 7.48-7.36 (m, 2H), 7.25-6.91 (m, 6H), 6.40-6.15 (m, 1H),6.09-5.82 (m, 1H), 3.60-2.53 (m, 7H), 2.23-2.07 (m, 3H), 1.92-1.15 (m,6H).

Example 311:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(6-phenoxypyridazin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 6-Phenoxypyridazin-3-amine

A solution of 6-chloropyridazin-3-amine (1.295 g, 10.00 mmol), phenol(3.764 g, 40.00 mmol) and NaOH (1.6 g, 40 mmol) in water (10 mL) wasstirred at 190° C. in a sealed tube for 16 hours. The mixture wasdispersed between EtOAc and water. The organic layer was collected,concentrated to dryness, and purified by flash column chromatography togive the title compound (0.5 g, 27% yield). MS (ESI): mass calcd. forC₁₀H₉N₃O, 187.20; m/z found, 188.0 [M+H]⁺.

Step B:(R)—N-(1-acryloylpyrrolidin-3-yl)-4-oxo-5-(6-phenoxypyridazin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-G in Example 1, and using 6-phenoxypyridazin-3-amine in place of2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (intermediate 5) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₆H₂₁N₇O₄S,527.6; m/z found, 528.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.24-8.18 (m,1H), 7.92-7.86 (m, 1H), 7.59 (d, J=9.2 Hz, 1H), 7.51-7.44 (m, 2H),7.32-7.24 (m, 3H), 6.67-6.54 (m, 1H), 6.30-6.23 (m, 2H), 5.77-5.72 (m,1H), 4.65-4.57 (m, 1H), 3.90-3.83 (m, 1H), 3.76-3.69 (m, 1H), 3.65-3.50(m, 2H), 2.36-2.25 (m, 1H), 2.22-2.12 (m, 1H).

Example 312:N-((3R,5S)-5-Methoxy-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:N-((3R,5S)-5-Methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(3R,5S)-3-amino-5-methoxypiperidine-1-carboxylate (Intermediate 29) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₇N₅O₄S,529.61; m/z found, 530.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.38-8.31(m, 1H), 7.45-7.36 (m, 2H), 7.33-7.26 (m, 1H), 7.22-7.12 (m, 1H),7.12-7.04 (m, 3H), 7.02-6.93 (m, 1H), 6.14-6.05 (m, 1H), 4.48-4.38 (m,1H), 3.82-3.72 (m, 1H), 3.52 (s, 3H), 3.40-3.31 (m, 2H), 3.28-3.19 (m,2H), 2.27-2.17 (m, 1H), 2.16-2.08 (m, 3H), 2.07-2.00 (m, 1H).

Step B:N-((3R,5S)-5-Methoxy-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution ofN-((3R,5S)-5-methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(50 mg, 0.09 mmol) in DCM (5 mL) were added formaldehyde (1 mL, 37 wt. %in H₂O) and NaBH(OAc)₃ (40 mg, 0.19 mmol) and was reacted at rt for 30min. The reaction was quenched by the addition of H₂O (10 mL), extractedwith DCM, dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was purified by flash column chromatography to givethe title compound as a yellow solid (40 mg, 82%). MS (ESI): mass calcd.for C₂₉H₂₉N₅O₄S, 543.6; m/z found, 544.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.37-8.30 (m, 1H), 7.45-7.37 (m, 2H), 7.33-7.26 (m, 1H),7.21-7.14 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.92 (m, 1H), 6.12-6.05 (m,1H), 4.38-4.26 (m, 1H), 3.71-3.58 (m, 1H), 3.46 (s, 3H), 3.01-2.62 (m,4H), 2.53 (s, 3H), 2.18-2.08 (m, 3H), 2.07-2.00 (m, 1H), 1.86-1.72 (m,1H).

Example 313:(R,EZ)—N-(1-(3-Cyclopropyl-2-(trifluoromethyl)acryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (EZ)-3-Cyclopropyl-2-(trifluoromethyl)prop-2-enoic acid

To a round bottom flask were added 3,3,3-trifluoropropanoic acid (500mg, 3.9 mmol), cyclopropanecarbaldehyde (274 mg, 3.91 mmol), piperidine(33 mg, 0.39 mmol), and pyridine (8 mL) and was stirred at 100° C. for 2h under N₂. The mixture was purified by HPLC to give the title compoundas a brown solid (53 mg, 7.5% yield). MS (ESI): mass calcd. forC₇H₇F₃O₂, 180.12; m/z found, 180.1 [M+H]⁺.

Step B:(R,EZ)—N-(1-(3-Cyclopropyl-2-(trifluoromethyl)acryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.28 mmol),(EZ)-3-cyclopropyl-2-(trifluoromethyl)prop-2-enoic acid (53 mg, 0.29mmol), HATU (148 mg, 0.390 mmol), and diisopropylethylamine (77 mg, 0.60mmol) in DMF (5 mL) was stirred at rt for 2 h. The mixture was purifiedby HPLC, then by preparative TLC to give the title compound as a whitesolid (15 mg, 8.2% yield), a mixture of two isomer (16.81% and 83.19%).MS (ESI): mass calcd. for C₃₄H₃₀F₃N₅O₄S, 661.7; m/z found, 662.0 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ 8.40-8.30 (m, 1H), 7.48-7.37 (m, 2H),7.36-7.28 (m, 1H), 7.23-7.15 (m, 1H), 7.14-7.04 (m, 3H), 7.03-6.94 (m,1H), 6.15-6.03 (m, 1H), 5.94-5.07 (m, 1H), 4.56-4.21 (m, 1H), 4.10-3.77(m, 2H), 3.24-2.89 (m, 2H), 2.13 (s, 3H), 2.12-2.03 (m, 1H), 1.98-1.83(m, 2H), 1.82-1.51 (m, 2H), 1.14-0.99 (m, 2H), 0.95-0.63 (m, 2H).

Example 314:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 2-methylaniline in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₃H₂₁N₅O₃S, 447.5; m/z found, 448.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ 8.26 (d, J=5.5, 1H),7.46-7.26 (m, 4H), 6.63-6.47 (m, 1H), 6.22-6.11 (m, 1H), 5.86 (d, J=5.5,1H), 5.69-5.57 (m, 1H), 4.61-4.44 (m, 1H), 3.91-3.40 (m, 4H), 2.25-2.10(m, 1H), 2.08 (s, 3H), 2.06-1.95 (m, 1H).

Example 315:5-(2-Methyl-4-phenoxyphenyl)-N-(2-morpholino-2-oxoethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: Methyl2-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)acetate

The title compound was prepared using analogous conditions described inMethod 1, steps A-G in Example 1, and using methyl 2-aminoacetate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:2-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)aceticacid

A solution of methyl2-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)acetate(1017 mg, 2.082 mmol) and NaOH (250 mg, 6.25 mmol) in MeOH/water (5 mL/5mL) was stirred at reflux for 4 hours. The reaction was concentratedunder vacuo to half volume and the pH was adjusted to pH=6 with AcOH.The precipitate was collected by filtration and dried under vacuo togive the title compound (949 mg), which was used in the next stepwithout further purification.

Step C:5-(2-Methyl-4-phenoxyphenyl)-N-(2-morpholino-2-oxoethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of2-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)aceticacid (150 mg, 0.32 mmol) and morpholine (42 mg, 0.48 mmol) in DMF (3 mL)were added HATU (240 mg, 0.63 mmol) and triethylamine (96 mg, 0.95 mmol)and was stirred at rt for 16 hours. The mixture was purified by flashcolumn chromatography to give the title compound (139 mg, 89% yield). MS(ESI): mass calcd. for C₂₈H₂₅N₅O₅S, 543.6; m/z found, 544.2 [M+H]⁺. 1HNMR (400 MHz, DMSO-d6): δ 8.35 (br, 1H), 8.30 (d, J=5.4 Hz, 1H),7.47-7.39 (m, 2H), 7.35 (d, J=8.7 Hz, 1H), 7.21-7.16 (m, 1H), 7.14-7.08(m, 2H), 7.08-7.05 (m, 1H), 6.96 (dd, J=8.7, 2.8 Hz, 1H), 5.93 (d, J=5.2Hz, 1H), 4.11 (d, J=5.8 Hz, 2H), 3.62-3.53 (m, 4H), 3.51-3.42 (m, 4H),2.05 (s, 3H).

Example 316:(R)—N-(1-Methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: tert-butyl(R)-3-(5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared in a manner analogous to Method 1, StepG (2) in Example 1 by using5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 84) and tert-butyl(R)-3-aminopiperidine-1-carboxylate in place of5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate.

Step B:(R)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of tert-butyl(R)-3-(5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(13 g, 24.2 mmol) in TFA (100 mL) was stirred at rt for 30 min, thenheated at 160° C. for 8 hr in a sealed tube, cooled to room temperatureand concentrated to give a yellow solid used in the next step withoutfurther purification (7.6 g).

Step C:(R)—N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamideformate

A mixture of(R)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(7.6 g, 23.9 mmol) and formaldehyde (10 mL, 37 wt. % in H₂O) in methanol(50 mL) was added NaBH(OAc)₃ (25.4 g, 119.7 mmol) then stirred at roomtemperature for 16 hr, concentrated and purified by flash chromatographyeluting with MeOH/water (containing 0.1% HCOOH) to get the targetcompound as a yellow solid (5.8 g, 75%). MS (ESI): mass calcd. forC₁₆H₁₉N₅O₄S, 377.4; m/z found, 322.0 [M−HCOOH+H]⁺. ¹H NMR (400 MHz,D₂O): δ 8.46 (s, 1H), 8.04 (d, J=5.5 Hz, 1H), 6.39 (d, J=5.5 Hz, 1H),4.30-4.03 (m, 1H), 3.72-3.53 (m, 2H), 3.05-2.93 (m, 4H), 2.93-2.81 (m,1H), 2.25-2.02 (m, 2H), 2.00-1.80 (m, 1H), 1.72-1.50 (m, 1H).

Example 317:(R)-5-(2,6-Dimethyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 5-fluoro-1,3-dimethyl-2-nitrobenzene inplace of 5-fluoro-2-nitrotoluene in step A, and using(3R)-1-methylpiperidin-3-amine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₉H₂₉N₅O₃S, 527.6; m/z found, 528.7[M+H]⁺. 1H NMR (400 MHz, a mixture of CD₃OD and DMSO-d6): δ 8.32 (d,J=5.5 Hz, 1H), 7.41-7.34 (m, 2H), 7.17-7.10 (m, 1H), 7.08-7.02 (m, 2H),6.87-6.82 (m, 2H), 5.96 (d, J=5.5 Hz, 1H), 4.20-4.17 (m, 1H), 4.00-3.88(m, 1H), 3.41-3.28 (m, 1H), 3.26-3.16 (m, 1H), 2.83-2.67 (m, 4H), 2.01(s, 6H), 1.97-1.86 (m, 2H), 1.81-1.69 (m, 1H), 1.67-1.52 (m, 1H).

Example 318:(R)—N-(1-(3-Hydroxypropanoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*R)-(2-Methyl-4-phenoxyphenl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 300, 60 mg, 0.11 mmol), 3-hydroxypropanoic acid (20 mg, 0.22mmol), HATU (55 mg, 0.15 mmol), and diisopropylethylamine (35 mg, 0.28mmol) in DMF (5 mL) was stirred at rt for 2 h. The mixture was purifiedby flash column chromatography to give the title compound as a whitesolid (29 mg, 46% yield). MS (ESI): mass calcd. for C₃₀H₂₉N₅O₅S, 571.6;m/z found, 572.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.37-8.30 (m, 1H),7.44-7.37 (m, 2H), 7.33-7.27 (m, 1H), 7.21-7.14 (m, 1H), 7.12-7.03 (m,3H), 7.01-6.95 (m, 1H), 6.11-6.05 (m, 1H), 4.51-3.90 (m, 3H), 3.88-3.79(m, 2H), 3.20-3.05 (m, 1H), 2.90-2.75 (m, 1H), 2.73-2.60 (m, 2H), 2.12(s, 3H), 2.09-2.01 (m, 1H), 1.91-1.77 (m, 1H), 1.77-1.64 (m, 1H),1.64-1.49 (m, 1H).

Example 319:(R)-5-(*S)-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 5-chlorobenzo[d][1,3]dioxol-4-amine in placeof in place of 2-methyl-4-phenoxyaniline in step C, and using(R)-tert-butyl 3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, and using analogous conditions as described in Example 52, stepB, and using(R)-5-(*S)-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamidein place of(R)-5-(4-(2,6-difluorophenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.MS (ESI): mass calcd. for C₂₂H₂₀ClN₅O₄S, 485.94; m/z found, 486.5[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.40 (d, J=5.3 Hz, 1H), 7.14 (d,J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.27 (d, J=5.4 Hz, 1H), 6.10 (d,J=2.2 Hz, 2H), 4.34-4.21 (m, 1H), 3.52-3.42 (m, 1H), 3.28-3.21 (m, 1H),2.92-2.82 (m, 2H), 2.79 (s, 3H), 2.08-1.99 (m, 2H), 1.91-1.80 (m, 1H),1.78-1.64 (m, 1H).

Example 320:(R)—N-(1-Ethylpiperidin-3-yl)-5-(4-(2-isopropylphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(2-Isopropylphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using 2-isopropylphenol in placeof phenol in step A, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₃₁N₅O₃S, 541.66; m/z found, 542.2[M+H]⁺.

Step B:(R)—N-(1-Ethylpiperidin-3-yl)-5-(4-(2-isopropylphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(2-isopropylphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.19 mmol) and acetaldehyde (0.3 mL) in MeOH (6 mL) was addedNaBH(OAc)₃ (118 mg, 0.555 mmol) and was stirred at rt for 1 h,concentrated to dryness and purified by flash column chromatography togive the title compound as a white solid (72 mg, 60% yield). MS (ESI):mass calcd. for C₃₂H₃₅N₅O₃S, 569.7; m/z found, 570.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OH): δ 8.49 (s, 1H), 8.36-8.25 (m, 1H), 7.45-7.34 (m, 1H),7.32-7.24 (m, 1H), 7.24-7.15 (m, 2H), 7.03-6.92 (m, 2H), 6.91-6.83 (m,1H), 6.10-5.97 (m, 1H), 4.35-4.22 (m, 1H), 3.58-3.42 (m, 1H), 3.29-3.20(m, 2H), 3.12-2.97 (m, 2H), 2.85-2.64 (m, 2H), 2.09 (s, 3H), 2.06-1.98(m, 2H), 1.90-1.77 (m, 1H), 1.74-1.61 (m, 1H), 1.34-1.27 (m, 3H), 1.23(d, J=6.9 Hz, 6H).

Example 321:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps C-I in Example 1 (including Chiral Resolution Method Aafter step F to obtain the *R atropisomer), and using5-chlorobenzo[d][1,3]dioxol-4-amine in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₄H₂₀ClN₅O₅S, 526.0; m/z found, 526.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.37 (d, J=5.5 Hz, 1H), 7.11 (d,J=8.4 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.85-6.70 (m, 1H), 6.24 (d, J=5.5Hz, 1H), 6.23-6.13 (m, 1H), 6.10-6.06 (m, 2H), 5.77-5.66 (m, 1H),4.55-4.49 (m, 0.5H), 4.31-4.24 (m, 0.5H), 4.20-4.12 (m, 0.5H), 4.03-3.90(m, 1.5H), 3.23-3.11 (m, 1H), 2.97-2.84 (m, 1H), 2.10-2.01 (m, 1H),1.91-1.82 (m, 1H), 1.79-1.67 (m, 1H), 1.62-1.49 (m, 1H).

Example 322:(R)-5-(4-Cyclopropoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-Cyclopropoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using 3-methyl-4-nitrophenol andbromocyclopropane in place of phenol and 5-fluoro-2-nitrotoluene in stepA, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)-5-(4-Cyclopropoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(4-cyclopropoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(120 mg, 0.26 mmol), formaldehyde (0.5 mL, 37 wt. % in H₂O), andNaBH(OAc)₃ (83 mg, 0.39 mmol) in DCM (5 mL) was stirred at rt for 5 h.The mixture was concentrated to dryness and purified by flash columnchromatography to give the title compound as a light yellow solid (45mg, 36%). MS (ESI): mass calcd. for C₂₅H₂₇N₅O₃S, 477.6; m/z found, 478.0[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.41 (s, 1H), 8.32-8.27 (m, 1H),7.26-7.20 (m, 1H), 7.13-7.10 (m, 1H), 7.10-7.05 (m, 1H), 6.04-5.99 (m,1H), 4.34-4.24 (m, 1H), 3.88-3.79 (m, 1H), 3.53-3.43 (m, 1H), 3.28-3.22(m, 1H), 2.92-2.82 (m, 2H), 2.82-2.75 (m, 3H), 2.11 (s, 3H), 2.06-1.95(m, 2H), 1.92-1.78 (m, 1H), 1.76-1.63 (m, 1H), 0.85-0.78 (m, 2H),0.75-0.68 (m, 2H).

Example 323:(S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G in Example 1 (including Chiral Resolution Method Aafter step F to obtain the *R atropisomer), and using(3S)-tetrahydrofuran-3-amine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₆H₂₂N₄O₄S, 486.5; m/z found, 487.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.28 (d, J=5.5 Hz, 1H), 7.44-7.35 (m,2H), 7.34-7.25 (m, 1H), 7.20-7.11 (m, 1H), 7.09-7.00 (m, 3H), 6.97-6.90(m, 1H), 6.03 (d, J=5.5 Hz, 1H), 4.62-4.48 (m, 1H), 4.02-3.89 (m, 2H),3.85-3.75 (m, 1H), 3.74-3.65 (m, 1H), 2.35-2.20 (m, 1H), 2.09 (s, 3H),2.05-1.94 (m, 1H).

Example 324:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxy-2-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-I in Example 1, and using4-fluoro-1-nitro-2-(trifluoromethyl)benzene in place of5-fluoro-2-nitrotoluene in step A, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₉H₂₂F₃N₅O₄S, 593.6; m/z found, 594.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.39 (s, 1H), 8.54-8.18 (m, 2H),7.74 (d, J=8.7 Hz, 1H), 7.60-7.37 (m, 4H), 7.34-7.14 (m, 3H), 6.70-6.45(m, 1H), 6.23-5.97 (m, 2H), 5.74-5.55 (m, 1H), 4.63-4.35 (m, 1H),3.95-3.38 (m, 4H), 2.27-1.87 (m, 2H).

Example 325:(R)-5-(*R)-(2-Methyl-4-phenoxyphenl)-4-oxo-N-(1-propionylpyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1 (including Chiral Resolution Method Aafter step F to obtain the *R atropisomer), and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(60 mg, 0.12 mmol) and triethylamine (30 mg, 0.3 mmol) in DCM (2 mL) wasadded propanoyl propanoate (39 mg, 0.3 mmol) in DCM was added dropwiseand was stirred for 2 h at rt, then it was concentrated to dryness. Theresidue was purified by flash column chromatography, then preparativeTLC to give the title compound as a yellow solid (14 mg). MS (ESI): masscalcd. for C₂₉H₂₇N₅O₄S, 541.6; m/z found, 542.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 10.24 (s, 1H), 8.72-8.48 (br, 1H), 8.30-8.17 (m, 1H),7.48-7.41 (m, 2H), 7.32-7.24 (m, 1H), 7.23-7.17 (m, 1H), 7.15-7.10 (m,2H), 7.09-7.05 (m, 1H), 6.99-6.94 (m, 1H), 5.92-5.77 (m, 1H), 4.56-4.35(m, 1H), 3.81-3.31 (m, 4H), 2.30-2.22 (m, 2H), 2.21-2.08 (m, 1H), 2.05(s, 3H), 2.01-1.87 (m, 1H), 1.02-0.96 (m, 3H).

Example 326:(R)-5-(4-(2-Carbamoylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-(2-Carbamoylphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using 2-hydroxybenzamide in placeof phenol in step A, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)-5-(4-(2-Carbamoylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-(2-carbamoylphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(315 mg, 0.116 mmol) in DCM were added formaldehyde (1.0 mL, 37 wt. % inH₂O) and NaBH(OAc)₃ (49 mg, 0.23 mmol) and was stirred at roomtemperature for 4 hours. To the mixture were added DCM (50 mL), MeOH (5mL), water (30 mL), and an aqueous solution of NH₄OH (2 mL). The organiclayer was collected, concentrated to dryness, and purified by flashcolumn chromatography to give the title compound as a yellow solid (17mg, 26% yield). MS (ESI): mass calcd. for C₂₉H₂₈N₆O₄S, 556.6; m/z found,557.4 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 10.82 (br, 1H), 8.25 (d,J=5.3 Hz, 1H), 8.18-8.03 (m, 1H), 7.95 (d, J=6.9 Hz, 1H), 7.85-7.76 (m,1H), 7.76-7.67 (m, 1H), 7.45-7.36 (m, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.97(d, J=8.3 Hz, 1H), 6.92 (t, J=7.6 Hz, 1H), 5.86 (d, J=5.4 Hz, 1H),3.96-3.91 (m, 1H), 2.85-2.79 (m, 1H), 2.68-2.62 (m, 1H), 2.20 (s, 3H),2.08 (s, 3H), 1.95-1.86 (m, 2H), 1.82-1.74 (m, 1H), 1.72-1.65 (m, 1H),1.57-1.47 (m, 1H), 1.37-1.29 (m, 1H).

Example 327:5-(2-Methyl-4-phenoxyphenyl)-2-(piperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

To a solution of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27, 1.50 g, 3.59 mmol) in 1-methyl-2-pyrrolidinone(15 mL) was added silver acetate (120 mg, 0.72 mmol) and potassiumcarbonate (149 mg, 1.08 mmol) and was stirred at 120° C. for 30 minutes.The reaction was filtered and the organic layer was collected andconcentrated to dryness. The residue was purified by flash columnchromatography (SiO₂) to give the title compound (1.2 g, 89% yield).

Step C:2-Chloro-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

To a solution of5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one(1000 mg, 2.68 mmol) in CHCl₃ (20 mL) was added NCS (358 mg, 2.68 mmol)and was stirred overnight at 15° C. The reaction was poured into aqueousNaHCO₃ (25 mL) and extracted with DCM (30 mL×3). The combined organiclayers were washed with brine (50 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness. The residue was purified by flashcolumn chromatography (SiO₂) to give the title compound (1.0 g, 92%yield).

Step D: tert-Butyl4-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperazine-1-carboxylate

To a solution of2-chloro-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one(200 mg, 0.49 mmol) in DMSO (3 mL) were added 1-Boc-piperazine (913 mg,4.90 mmol), Cu (6.4 mg, 0.10 mmol), copper(I) iodide (19 mg, 0.10 mmol),and potassium phosphate (312 mg, 1.47 mmol) and was irradiated using amicrowave at 120° C. for 2.5 h. The reaction was poured into citric acid(25 mL, 4 M in water) and extracted with dichloromethane (30 mL×3). Thecombined organic layers were concentrated to dryness and the residue waspurified by preparative RP-C18 HPLC to give the title compound (40 mg).

Step E:5-(2-Methyl-4-phenoxyphenyl)-2-(piperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

A solution of tert-butyl4-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperazine-1-carboxylate(30 mg, 0.054 mmol) in MeOH (1 mL) and concentrated HCl (1 mL) and wasstirred at room temperature for 3 h. The mixture was poured into aqueousNaHCO₃ (50 mL), extracted with DCM (3×30 mL), the organic phases washedwith saturated brine (50 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by preparative RP-C18HPLC to give the title compound as a trifluoroacetic acid salt (12 mg,96% yield). MS (ESI): mass calcd. for C₂₅H₂₃N₅O₂S, 457.5; m/z found,458.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.67 (s, 1H), 8.77 (br, 2H),8.17 (d, J=5.4 Hz, 1H), 7.45 (t, J=7.8 Hz, 2H), 7.33 (d, J=8.5 Hz, 1H),7.20 (t, J=7.3 Hz, 1H), 7.15-7.05 (m, 3H), 6.98 (dd, J=2.8, 8.4 Hz, 1H),5.85 (d, J=5.4 Hz, 1H), 3.36-3.18 (m, 4H), 3.16-2.98 (m, 4H), 2.06 (s,3H).

Example 328:(R)-6-Methyl-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using2-chloro-4-iodo-5-methylpyridine-3-carbonitrile and 4-phenoxyaniline inplace of 2-chloro-4-iodopyridine-3-carbonitrile and2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.3[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.20 (s, 1H), 7.38-7.47 (m, 4H),7.16-7.21 (m, 1H), 7.08-7.13 (m, 4H), 4.21-4.31 (m, 1H), 3.53 (dd,J=4.04, 12.13 Hz, 1H), 3.33-3.40 (m, 1H), 2.88-3.01 (m, 2H), 2.01-2.13(m, 2H), 1.67-1.91 (m, 2H), 1.61 (s, 3H).

Example 329:(R)—N-(1-Cyanopiperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 300, 52.5 mg, 0.105 mmol), BrCN (13.4 mg, 0.126 mmol), andtriethylamine (21 mg, 0.21 mmol) in DCM (5 mL) was stirred at rt for 4hours. The reaction mixture was concentrated to dryness and purified byflash column chromatography to give the title compound as a yellow solid(30 mg, 53% yield). MS (ESI): mass calcd. for C₂₈H₂₄N₆O₃S, 524.6; m/zfound, 525.3 [M+H]+. ¹H NMR (400 MHz, CD3OD and DMSO-d₆): δ 8.29-8.22(m, 1H), 7.39-7.31 (m, 2H), 7.28-7.22 (m, 1H), 7.14-7.08 (m, 1H),7.07-7.01 (m, 2H), 7.01-6.98 (m, 1H), 6.92-6.88 (m, 1H), 5.98-5.90 (m,1H), 3.99-3.95 (m, 2H), 3.44-3.39 (m, 1H), 3.27-3.21 (m, 1H), 2.97-2.87(m, 2H), 2.02 (s, 3H), 1.90-1.84 (m, 1H), 1.79-1.72 (m, 1H), 1.68-1.60(m, 1H), 1.56-1.48 (m, 1H).

Example 330:(R)-5-(3,5-Dichlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 3,5-dichloroaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₀H₁₇Cl₂N₅O₂S, 462.4; m/z found,461.9 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J=7.2 Hz, 1H), 8.22(s, 1H), 8.15 (d, J=5.5 Hz, 1H), 7.73 (t, J=1.7 Hz, 1H), 7.51 (s, 2H),5.95 (d, J=5.6 Hz, 1H), 4.06 (s, 1H), 3.31-3.27 (m, 1H), 3.14-3.10 (m,1H), 2.87-2.73 (m, 2H), 1.96-1.93 (m, 1H), 1.88-1.84 (m, 1H), 1.71-1.52(m, 2H).

Example 331:(R)—N-Methyl-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as describedin Method 1, steps A-H in Example 1, and using (R)-tert-butyl3-(methylamino)pyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.2[M+H]⁺. ¹H NMR (400 MHz, CD3OD and DMSO-d₆): δ 8.27 (d, J=5.5 Hz, 1H),7.45-7.33 (m, 2H), 7.28 (d, J=8.6 Hz, 1H), 7.17-7.12 (m, 1H), 7.11-7.00(m, 3H), 6.97-6.87 (m, 1H), 5.96 (d, J=5.5 Hz, 1H), 4.75-4.53 (m, 1H),3.53-3.41 (m, 1H), 3.40-3.30 (m, 2H), 3.14 (s, 3H), 2.32-1.86 (m, 6H).

Example 332:(R)-5-(4-Isopropoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 70, 100 mg, 0.22 mmol) in DCM (5 mL) and was treated withformaldehyde (0.5 mL, 37 wt. % in H₂O). To the stirred reaction mixturewas added NaBH(OAc)₃ (91 mg, 0.43 mmol) and was stirred at rt for 1 h,then concentrated to dryness. The residue was purified by flash columnchromatography to give the title compound as a yellow solid (27 mg, 26%yield). MS (ESI): mass calcd. for C₂₅H₂₉N₅O₃S, 479.6; m/z found, 480.2[M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 8.24 (d, J=5.4 Hz, 1H), 8.04 (s,1H), 7.25-7.13 (m, 1H), 6.99-6.93 (m, 1H), 6.92-6.83 (m, 1H), 5.89-5.78(m, 1H), 4.73-4.59 (m, 1H), 3.96-3.88 (m, 1H), 2.85-2.76 (m, 1H),2.68-2.61 (m, 1H), 2.18 (s, 3H), 2.01 (s, 3H), 1.92-1.64 (m, 5H),1.55-1.45 (m, 1H), 1.31-1.26 (m, 6H).

Example 333:(R)-5-(4-Ethoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as describedin Method 1, steps A-Gin Example 1, and using 3-methyl-4-nitrophenol andbromoethane in place of phenol and 5-fluoro-2-nitrotoluene in step A,and using (3R)-1-methylpiperidin-3-amine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₄H₂₇N₅O₃S, 465.6; m/z found, 466.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.44 (s, 1H), 8.30 (d, J=5.5 Hz, 1H),7.26-7.15 (m, 1H), 7.01-6.95 (m, 1H), 6.95-6.87 (m, 1H), 6.02 (d, J=5.5Hz, 1H), 4.33-4.18 (m, 1H), 4.14-4.03 (m, 2H), 3.51-3.37 (m, 1H),3.27-3.14 (m, 1H), 2.85-2.65 (m, 5H), 2.10 (s, 3H), 2.06-1.94 (m, 2H),1.90-1.73 (m, 1H), 1.72-1.57 (m, 1H), 1.45-1.37 (m, 3H).

Example 334:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(tert-butyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 4-(tert-butyl)aniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₉N₅O₃S, 503.6; m/z found, 504.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.21 (d, J=15.1 Hz, 1H), 8.34 (d,J=5.5 Hz, 1H), 8.18-8.05 (m, 1H), 7.63 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.5Hz, 2H), 6.90-6.73 (m, 1H), 6.12 (d, J=17.0 Hz, 1H), 6.00 (d, J=5.5 Hz,1H), 5.70 (d, J=10.7 Hz, 1H), 4.53-4.19 (m, 1H), 4.11-3.95 (m, 1H), 3.80(s, 1H), 3.18-2.93 (m, 1H), 2.82-2.63 (m, 1H), 2.01-1.91 (m, 1H),1.85-1.58 (m, 2H), 1.44 (s, 1H), 1.36 (s, 9H).

Example 335:(R)-5-(*S)-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 343, steps A-B, and by obtaining the *S atropisomer instead ofthe *R atropisomer in step A. MS (ESI): mass calcd. for C₂₇H₃₁N₅O₄S,521.63; m/z found, 522.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.41 (s,1H), 8.34-8.28 (m, 1H), 7.25-7.16 (m, 1H), 7.06-7.01 (m, 1H), 7.00-6.95(m, 1H), 6.06-6.01 (m, 1H), 4.70-4.61 (m, 1H), 4.34-4.22 (m, 1H),4.03-3.90 (m, 2H), 3.68-3.56 (m, 2H), 3.52-3.40 (m, 1H), 2.90-2.70 (m,5H), 2.16-1.95 (m, 8H), 1.88-1.81 (m, 1H), 1.81-1.63 (m, 3H).

Example 336:(R)-5-(3-Chlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 3-chloroaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₀H₁₈ClN₅O₂S, 427.9; m/z found, 427.8[M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J=7.3 Hz, 1H), 8.22 (s,1H), 8.16 (d, J=5.6 Hz, 1H), 7.61-7.54 (m, 2H), 7.48 (s, 1H), 7.34 (d,J=7.5 Hz, 1H), 5.88 (d, J=5.6 Hz, 1H), 4.06 (s, 1H), 3.30-3.26 (m, 1H),3.12-3.09 (m, 1H), 2.82-2.73 (m, 2H), 1.95-1.93 (m, 1H), 1.87-1.83 (m,1H), 1.72-1.53 (m, 2H).

Example 337:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-phenyl-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:4-Oxo-5-phenyl-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared using analogous conditions as describedin Method 1, steps C-F in Example 1, and using aniline in place of2-methyl-4-phenoxyaniline in step C.

Step B:4-Oxo-5-phenyl-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride

To a solution of4-oxo-5-phenyl-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (200 mg, 0.64 mmol) in DCM (10 mL) was added oxalyl dichloride (4mL) and was stirred at 60° C. overnight. The reaction mixture wasconcentrated to dryness to give the title compound as a brown solid (200mg, 95% yield).

Step C: (R)-tert-Butyl3-(4-oxo-5-phenyl-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidine-1-carboxylate

To a solution of4-oxo-5-phenyl-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride (200 mg, 0.61 mmol) in DCM (4 mL) were added tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate (200 mg, 1.07 mmol) andtriethylamine (100 mg, 0.99 mmol) and was reacted at rt for 20 min. Thereaction was quenched with H₂O (10 mL), extracted with DCM, dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue waspurified by flash column chromatography and preparative TLC to give thetitle compound as a yellow solid 150 mg, 52% yield).

Step D:(R)-4-Oxo-5-phenyl-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (R)-tert-butyl3-(4-oxo-5-phenyl-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidine-1-carboxylate(150 mg, 0.31 mmol) in MeOH (5 mL) was added concentrated HCl (2 mL) andwas reacted at rt for 20 min. The reaction was quenched by the additionof H₂O (10 mL), extracted with DCM, dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness. The residue was purified by flashcolumn chromatography and preparative TLC to give the title compound asa red solid (100 mg, 84% yield).

Step E:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-phenyl-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-4-oxo-5-phenyl-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.26 mmol) in DCM (4 mL) were added prop-2-enoyl chloride (25mg, 0.28 mmol) and triethylamine (45 mg, 0.45 mmol) and was reacted atrt for 20 min. The reaction was quenched by the addition of H₂O (10 mL),extracted with DCM, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by flash columnchromatography and preparative TLC to give the title compound as a redsolid (105 mg, 91.6% yield). MS (ESI): mass calcd. for C₂₂H₁₉N₅O₃S,433.5; m/z found, 434.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.28-8.24 (m,1H), 7.62-7.54 (m, 3H), 7.46-7.40 (m, 2H), 6.66-6.52 (m, 1H), 6.32-6.22(m, 1H), 6.09-6.05 (m, 1H), 5.78-5.69 (m, 1H), 4.68-4.56 (m, 1H),4.03-3.68 (m, 3H), 3.59-3.49 (m, 1H), 2.32-2.07 (m, 2H).

Example 338:(R)—N-Methyl-5-(2-methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)—N-Methyl-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as describedin Method 1, steps A-H in Example 1, and using tert-butyl(3R)-3-(methylamino)pyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)—N-Methyl-5-(2-methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)—N-methyl-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.19 mmol) and formaldehyde (0.5 mL, 37 wt. % in H₂O) in MeOH(30 mL) was added NaBH(OAc)₃ (120 mg, 0.57 mmol) and was stirred at rtfor 3 h, concentrated to dryness, and purified by flash columnchromatography to give the title compound as a white solid (67 mg, 99%yield). MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.6; m/z found, 514.6[M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 8.29 (d, J=5.4 Hz, 1H), 7.50-7.40(m, 2H), 7.37 (d, J=8.6 Hz, 1H), 7.22-7.15 (m, 1H), 7.13-7.05 (m, 3H),6.98-6.92 (m, 1H), 5.95 (d, J=5.4 Hz, 1H), 4.95-4.77 (m, 1H), 3.05 (s,3H), 2.81-2.69 (m, 2H), 2.46-2.35 (m, 1H), 2.22 (s, 3H), 2.20-2.07 (m,2H), 2.05 (s, 3H), 1.92-1.77 (m, 1H).

Example 339:(S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as describedin Method 1, steps A-H in Example 1 (including Chiral Resolution MethodA after step F to obtain the *R atropisomer), and using(S)-1-boc-3-aminopiperidine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To an oven dried microwave vial containing a stir bar under Ar wereadded(S)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(59.9 mg, 0.12 mmol), sodium cyanoborohydride (18 mg, 0.29 mmol), andMeOH (4 mL) and the flask was cooled to 0° C. in an ice bath. Next,aqueous formaldehyde (0.01 mL, 37 wt. % in H₂O) was added via syringethrough the septum cap and the reaction was allowed to slowly warm to rtand stir at rt for 30 min. The reaction mixture was purified by HPLC togive the title compound (14.7 mg, 23.9% yield). MS (ESI): mass calcd.for C₂₈H₂₇N₅O₃S, 513.6; m/z found, 514.0 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD): δ 8.16 (d, J=5.6 Hz, 1H), 7.29 (s, 2H), 7.18 (d, J=8.6 Hz, 1H),7.12-6.80 (m, 5H), 5.90 (d, J=5.5 Hz, 1H), 4.13-3.51 (m, 2H), 2.92-2.74(m, 1H), 2.69-2.52 (m, 1H), 2.23 (s, 3H), 2.12-1.98 (m, 5H), 1.90-1.30(m, 5H).

Example 340:(R)-5-(4-Methoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as describedin Method 1, steps C-G in Example 1, and using 4-methoxy-2-methylanilinein place of 2-methyl-4-phenoxyaniline in step C, and using(3R)-1-methylpiperidin-3-amine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₃H₂₅N₅O₃S, 451.5; m/z found, 452.2[M+H]⁺. ¹H NMR (400 MHz, cd3od) δ 8.28 (d, J=5.5 Hz, 1H), 7.27-7.17 (m,1H), 7.06-6.97 (m, 1H), 6.97-6.88 (m, 1H), 6.05-5.91 (d, J=5.6 Hz, 1H),4.24-4.09 (m, 1H), 3.85 (s, 3H), 3.01-2.85 (m, 1H), 2.78-2.62 (m, 1H),2.34 (s, 3H), 2.25-2.14 (m, 2H), 2.12 (s, 3H), 1.93-1.76 (m, 2H),1.73-1.61 (m, 1H), 1.57-1.43 (m, 1H).

Example 341:(R)-4-Oxo-N-(piperidin-3-yl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 4-(trifluoromethyl)aniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₁H₁₈F₃N₅O₂S, 461.5; m/z found, 462.0[M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.31 (s, 1H), 9.11(s, 1H), 8.37-8.33 (m, 2H), 8.02 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.2 Hz,2H), 6.11 (d, J=5.6 Hz, 1H), 4.21 (s, 1H), 3.32-3.30 (m, 1H), 3.21-3.18(m, 1H), 2.94-2.81 (m, 2H), 1.92-1.89 (m, 2H), 1.81-1.58 (m, 2H).

Example 342:(R)-5-(4-Methoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 4-methoxyaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₁H₂₁N₅O₃S, 423.5; m/z found, 423.9[M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.28-8.20 (m, 2H),7.28 (d, J=7.2 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H), 5.89 (s, 1H), 4.05 (s,1H), 3.83 (s, 3H), 3.25-3.22 (m, 1H), 3.09-3.06 (m, 1H), 2.74 (brs, 2H),1.94-1.91 (m, 1H), 1.82 (brs, 1H), 1.60 (brs, 2H).

Example 343:(R)-5-(R)-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:R)-5-(R)-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as describedin Method 1, steps D-H in Example 1 (including Chiral Resolution MethodA after step F to obtain the *R atropisomer), and using2-chloro-4-(2-methyl-4-tetrahydropyran-4-yloxyanilino)pyridine-3-carbonitrile(Intermediate 31 in place of2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrile in step D,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G (216 mg).

Step B:(R)-5-(*R)-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*R)-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(80 mg, 0.16 mmol), formaldehyde (0.5 mL, 37 wt. % in H₂O), andNaBH(OAc)₃ (50 mg, 0.24 mmol) in DCM (5 mL) was stirred at rt for 5 h.The mixture was concentrated to dryness and purified by flash columnchromatography to give the title compound as a yellow solid (25 mg, 29%yield). MS (ESI): mass calcd. for C₂₇H₃₁N₅O₄S, 521.6; m/z found, 522.0[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.47 (s, 1H), 8.36-8.28 (m, 1H),7.27-7.16 (m, 1H), 7.09-6.95 (m, 2H), 6.08-6.01 (m, 1H), 4.70-4.61 (m,1H), 4.34-4.22 (m, 1H), 4.03-3.90 (m, 2H), 3.68-3.56 (m, 2H), 3.47-3.37(m, 1H), 2.81-2.70 (m, 5H), 2.16-1.95 (m, 8H), 1.87-1.63 (m, 4H).

Example 344:(R)-5-([1,1′-Biphenyl]-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-([1,1′-biphenyl]-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a 2-5 mL microwave vial with stir bar were added1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (5.4 mg, 0.0066 mmol),2-chloro-4-iodonicotinonitrile (86.7 mg, 0.328 mmol), 4-aminobiphenyl(56.8 mg, 0.336 mmol), and Cs₂CO₃ (151 mg, 0.463 mmol) at rt. The vialwas sealed, charged with dioxane (0.66 mL) via syringe, and quicklyevacuated/flushed with argon (4×). The mixture was stirred at 150° C.under argon for 30 min. The reaction was treated with (R)-tert-butyl3-(2-mercaptoacetamido)piperidine-1-carboxylate (Intermediate 22) (0.51mL, 0.65 M, 0.33 mmol) via syringe at rt, and stirred under argon at150° C. for 15 min. The mixture was then cooled to rt, opened, andtreated with CDI (218 mg, 1.34 mmol) in one portion under air. Themicrowave vial was resealed, evacuated/flushed with argon (4×), andstirred at 150° C. under argon for 15 min. The reaction was then cooledto rt, diluted with EtOAc (10 mL), and washed with 0.5 M citric acid(1×10 mL; final pH˜4-5), 0.1 M citric acid (1×10 mL; final pH˜2), and 2M K₂CO₃ (1×10 mL; final pH>10). The organic phase was dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue waspurified by flash column chromatography to give the title compound as ayellow foam (89.7 mg, 48%).

Step C:(R)-5-1,1R)-5-[1,1′-Biphenyl]-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-([1,1′-biphenyl]-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(86.6 mg, 0.152 mmol) in dioxane (0.76 mL, 0.2 M, 0.152 mmol) in an 8 mLreaction vial was stirred under air at rt while HCl (4 M in dioxane, 2mL, 8 mmol) was added dropwise over ˜1 min and then capped and stirredat rt for 1 h, filtered to collect the precipitate, washed with dioxane(1×2 mL), and concentrated to dryness to give the title compound as anoff-white powder (65.4 mg, 85.0%). MS (ESI): mass calcd. forC₂₆H₂₃N₅O₂S, 469.6; m/z found, 470.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δppm 8.47 (d, J=6.1 Hz, 1H), 7.90 (d, J=8.6 Hz, 2H), 7.71 (d, J=7.1 Hz,2H), 7.46-7.57 (m, 4H), 7.38-7.45 (m, 1H), 6.45 (d, J=6.6 Hz, 1H),4.24-4.35 (m, 1H), 3.55 (dd, J=12.1, 4.0 Hz, 1H), 3.37 (d, J=12.6 Hz,1H), 2.92-3.04 (m, 2H), 2.04-2.16 (m, 2H), 1.71-1.93 (m, 2H)

Example 345:(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(*R)(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 300, 50 mg, 0.10 mmol) in DCM (15 mL) were added triethylamine(30 mg) and acroyl chloride (26 mg, 0.20 mmol) and the mixture wasstirred for 30 min at rt. The mixture was purified by flash columnchromatography to give the title compound as yellow solid (31 mg, 56%yield). MS (ESI): mass calcd. for C₃₀H₂₉N₅O₄S, 555.6; m/z found, 556.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30 (d, J=5.5 Hz, 1H), 7.45-7.36 (m,2H), 7.34-7.26 (m, 1H), 7.22-7.13 (m, 1H), 7.12-7.01 (m, 3H), 7.01-6.93(m, 1H), 6.05 (d, J=5.5 Hz, 1H), 4.58-3.77 (m, 3H), 3.19-2.98 (m, 1H),2.83-2.66 (m, 1H), 2.58-2.17 (m, 2H), 2.12 (s, 3H), 2.08-2.00 (m, 1H),1.92-1.43 (m, 3H), 1.14-1.06 (m, 3H).

Example 346:(R)-5-(3,4-Dichlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 3,4-dichloroaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₀H₁₇Cl₂N₅O₂S, 462.4; m/z found,461.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): 8.72 (d, J=7.6 Hz, 1H), 8.20(s, 1H), 8.13 (d, J=4.6 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.70 (s, 1H),7.37 (dd, J=8.5, 1.5 Hz, 1H), 5.94 (d, J=5.1 Hz, 1H), 4.05 (s, 1H),3.31-3.27 (m, 1H), 3.13-3.10 (m, 1H), 2.86-2.71 (m, 2H), 1.95-1.84 (m,2H), 1.71-1.51 (m, 2H).

Example 347:(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 3-(trifluoromethyl)aniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₁H₁₈F₃N₅O₂S, 461.5; m/z found, 461.9[M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.22 (s, 1H), 8.15 (d,J=5.1 Hz, 1H), 7.88-7.72 (m, 3H), 7.68 (d, J=6.9 Hz, 1H), 5.85 (d, J=5.2Hz, 1H), 4.06 (s, 1H), 3.31-3.28 (m, 1H), 3.13-3.10 (m, 1H), 2.83-2.73(m, 2H), 1.97-1.94 (m, 1H), 1.88-1.84 (m, 1H), 1.72-1.51 (m, 2H).

Example 348:(R)-4-Oxo-5-phenyl-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using aniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₀H₁₉N₅O₂S, 393.5; m/z found, 394.0[M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.27 (s, 1H),8.19-8.15 (m, 1H), 7.59-7.56 (m, 2H), 7.51-7.47 (m, 1H), 7.36 (d, J=7.5Hz, 2H), 5.85-5.82 (m, 1H), 4.06 (s, 1H), 3.27-3.25 (m, 1H), 3.10-3.07(m, 1H), 2.75 (s, 2H), 1.95-1.93 (m, 1H), 1.86-1.83 (m, 1H), 1.66-1.57(m, 2H).

Example 349:(R)—N-(1-Methylpiperidin-3-yl)-4-oxo-5-(4-phenoxy-2-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-4-Oxo-5-(4-phenoxy-2-(trifluoromethyl)phenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as describedin Method 1, steps A-H in Example 1, and using4-fluoro-1-nitro-2-(trifluoromethyl)benzene in place of5-fluoro-2-nitrotoluene in step A, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)—N-(1-Methylpiperidin-3-yl)-4-oxo-5-(4-phenoxy-2-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-4-oxo-5-(4-phenoxy-2-(trifluoromethyl)phenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(150 mg, 0.25 mmol) and formaldehyde (1.0 mL, 37 wt. % in H₂O) in MeOH(20 mL) was added NaBH(OAc)₃ (162 mg, 0.764 mmol) and was stirred at rtfor 16 h, concentrated to dryness, and purified by flash columnchromatography to give the title compound as a light yellow solid (116mg, 80.3% yield). MS (ESI): mass calcd. for C₂₈H₂₄F₃N₅O₃S, 567.6; m/zfound, 568.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.35-8.25 (m, 1H),8.22-8.16 (m, 2H), 7.75-7.60 (m, 1H), 7.57-7.37 (m, 4H), 7.33-7.17 (m,3H), 6.00-5.90 (m, 1H), 4.10-3.83 (m, 1H), 3.00-2.85 (m, 1H), 2.83-2.63(m, 1H), 2.28 (s, 3H), 2.18-1.91 (m, 2H), 1.85-1.65 (m, 2H), 1.64-1.46(m, 1H), 1.46-1.28 (m, 1H).

Example 350:(R)-5-(4-Methyl-6-phenoxypyridazin-3-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-methyl-6-phenoxypyridazin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as describedin Method 1, steps A, and C-H in Example 1, and using6-chloro-4-methylpyridazin-3-amine in place of 5-fluoro-2-nitrotoluenein step A (with no step B), and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)-5-(4-Methyl-6-phenoxypyridazin-3-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-methyl-6-phenoxypyridazin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(20 mg, 0.040 mmol) in DCM (5 mL) were added formaldehyde (0.5 mL, 37wt. % in H₂O) and NaBH(OAc)₃ (34 mg, 0.16 mmol) and was stirred at roomtemperature for 4 hours. To the mixture was added DCM (50 mL), MeOH (5mL), and water (30 mL). The organic layer was collected, concentrated todryness, and purified by TLC to give the title compound as a yellowsolid (8 mg, 38% yield). MS (ESI): mass calcd. for C₂₆H₂₅N₇O₃S, 515.6;m/z found, 516.4 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 8.55 (br, 1H),8.16-8.10 (br, 1H), 7.74 (s, 1H), 7.50-7.44 (m, 2H), 7.34-7.24 (m, 3H),6.11-6.05 (br, 1H), 3.95-3.90 (m, 1H), 2.88-2.78 (m, 1H), 2.68-2.59 (m,1H), 2.40 (s, 3H), 2.22 (s, 3H), 2.05-1.93 (m, 2H), 1.84-1.76 (m, 1H),1.74-1.66 (m, 1H), 1.57-1.48 (m, 1H), 1.31-1.26 (m, 1H).

Example 351:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-methyl-6-phenoxypyridazin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as describedin Method 1, steps A, and C-G in Example 1, and using6-chloro-4-methylpyridazin-3-amine in place of 5-fluoro-2-nitrotoluenein step A (with no step B), and using1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (intermediate 5) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₃N₇O₄S,541.6; m/z found, 542.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.24-8.14(br, 1H), 7.78 (s, 1H), 7.53-7.42 (m, 2H), 7.36-7.22 (m, 3H), 6.66-6.50(m, 1H), 6.24-6.03 (m, 2H), 5.71-5.60 (m, 1H), 4.53-4.40 (m, 1H),3.91-3.82 (m, 1H), 3.74-3.62 (m, 3H), 2.40 (s, 3H), 2.21-1.85 (m, 2H).

Example 352:(R)—N-(1-Methylpiperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as describedin Method 1, steps C-G in Example 1, and using 2-methylaniline in placeof 2-methyl-4-phenoxyaniline in step C, and using(3R)-1-methylpiperidin-3-amine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₂H₂₃N₅O₂S, 421.5; m/z found, 422.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ 8.20 (d, J=5.1 Hz, 1H),7.45-7.29 (m, 3H), 7.28-7.21 (m, 1H), 5.83 (d, J=5.3 Hz, 1H), 4.09-3.99(m, 1H), 2.90-2.77 (m, 1H), 2.69-2.58 (m, 1H), 2.24 (s, 3H), 2.15-2.00(m, 5H), 1.84-1.65 (m, 2H), 1.62-1.49 (m, 1H), 1.46-1.33 (m, 1H).

Example 353:(R)-5-(*R)-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(*R)-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as describedin Method 1, steps C-H in Example 1 (including Chiral Resolution MethodA after step F to obtain the *R atropisomer), and using2,4-dichloropyridine-3-carbonitrile and 5-chloro-1,3-benzodioxol-4-aminein place of 2-methyl-4-phenoxyaniline and2-chloro-4-iodopyridine-3-carbonitrile in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₁H₁₈ClN₅O₄S, 471.92; m/z found,472.0 [M+H]⁺.

Step B:(R)-5-(*R)-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(*R)-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(103 mg, 0.218 mmol) and formaldehyde (0.3 mL, 37 wt. % in H₂O) in MeOH(6 mL) was added NaBH(OAc)₃ (92 mg, 0.44 mmol) and was stirred at rt for1 h, concentrated to dryness, and purified by flash columnchromatography to give the title compound as a white solid (18 mg, 17%yield). MS (ESI): mass calcd. for C₂₂H₂₀ClN₅O₄S, 485.9; m/z found, 486.5[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.39 (d, J=5.4 Hz, 1H), 7.13 (d,J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.26 (d, J=5.5 Hz, 1H), 6.10 (d,J=2.3 Hz, 2H), 4.33-4.20 (m, 1H), 3.45-3.34 (m, 1H), 3.25-3.13 (m, 1H),2.86-2.67 (m, 5H), 2.06-1.95 (m, 2H), 1.90-1.76 (m, 1H), 1.76-1.60 (m,1H).

Example 354:(R)-5-(2-Methyl-4-(pyridin-4-yloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-Methyl-4-(pyridin-4-yloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as describedin Method 1, steps A-H in Example 1, and using pyridin-4-ol in place ofphenol in step A, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)-5-(2-Methyl-4-(pyridin-4-yloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-(pyridin-4-yloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(110 mg, 0.22 mmol) and formaldehyde (0.3 mL, 37 wt. % in H₂O) in MeOH(5 mL) was added NaBH(OAc)₃ (140 mg, 0.66 mmol) and was stirred at rtfor 1 h, concentrated to dryness, and purified by flash columnchromatography to give the title compound as a white solid (72 mg, 64%yield). MS (ESI): mass calcd. for C₂₇H₂₆N₆O₃S, 514.6; m/z found, 515.5[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.40-8.24 (m, 1H), 8.17 (d, J=7.1 Hz,2H), 7.70 (s, 1H), 7.74-7.52 (m, 2H), 6.59 (d, J=7.1 Hz, 2H), 6.16-5.94(m, 1H), 4.30-4.14 (m, 1H), 3.29-3.17 (m, 1H), 3.09-2.09 (m, 1H),2.72-2.44 (m, 5H), 2.27 (s, 3H), 2.04-1.86 (m, 2H), 1.84-1.70 (m, 1H),1.65-1.49 (m, 1H).

Example 355:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 4-(trifluoromethyl)aniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₄H₂₀F₃N₅O₃S, 515.5; m/z found, 516.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.29 (d, J=16.5 Hz, 1H), 8.33 (d,J=5.5 Hz, 1H), 8.14-8.08 (m, 1H), 8.01 (d, J=8.5 Hz, 2H), 7.75 (d, J=8.2Hz, 2H), 6.78 (brs, 1H), 6.13-6.07 (m, 2H), 5.69 (d, J=10.1 Hz, 1H),4.54-4.16 (m, 1H), 4.10-3.74 (m, 2H), 3.05-2.94 (m, 1H), 2.80-2.73 (m,1H), 1.96-1.93 (m, 1H), 1.80-1.77 (m, 1H), 1.72-1.63 (m, 1H), 1.43 (s,1H).

Example 356:(R)-5-(3-(Dimethylamino)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 3-(dimethylamino)aniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₂H₂₄N₆O₂S, 436.5; m/z found, 437.0[M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J=7.6 Hz, 1H), 8.32 (s,1H), 8.22 (d, J=5.5 Hz, 1H), 7.38-7.34 (m, 1H), 6.83 (dd, J=8.4, 2.2 Hz,1H), 6.73-6.66 (m, 1H), 6.61 (d, J=7.5 Hz, 1H), 5.94 (d, J=5.5 Hz, 1H),4.09 (s, 1H), 3.26-3.22 (m, 1H), 3.13-3.03 (m, 1H), 2.92 (s, 6H),2.80-2.74 (m, 2H), 1.93-1.83 (m, 2H), 1.66-1.58 (m, 2H).

Example 357:(R)—N-(1-Acryloylpiperidin-3-yl)-5-isopropyl-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using propan-2-amine in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₀H₂₃N₅O₃S, 413.5; m/z found, 414.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.43-8.33 (m, 3H), 6.94 (d, J=8.5Hz, 1H), 6.85-6.74 (m, 1H), 6.13-6.07 (m, 1H), 5.68 (d, J=10.6 Hz, 1H),4.88 (s, 1H), 4.43-4.10 (m, 1H), 4.04-3.89 (m, 1H), 3.76 (s, 1H),3.13-2.85 (m, 3H), 1.95-1.93 (m, 1H), 1.80-1.77 (m, 1H), 1.61 (s, 1H),1.45 (d, J=6.8 Hz, 6H).

Example 358:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-Chloro-4-[(2-methyl-3-pyridyl)amino]pyridine-3-carbonitrile

To a 10-20 mL microwave vial were added sequentially2,4-dichloropyridine-3-carbonitrile (429 mg, 1.62 mmol),2-methylpyridin-3-amine (175 mg, 1.62 mmol), palladium(II) acetate (7.3mg, 0.032 mmol), bis(2-diphenylphosphinophenyl)ether (26 mg, 0.049mmol), and Cs₂CO₃ (740 mg, 2.27 mmol). The vial was sealed and wasevacuated and refilled with argon three times and dioxane (3.2 mL) wasadded. The vial was evacuated and refilled with argon once. Thesuspension was heated for 5 minutes in a 50° C. oil bath under argon andthen the sealed vial was heated for 30 minutes in a 150° C. oil bath.The suspension was removed from the heating bath and stored at roomtemperature overnight. The crude reaction mixture was used directly inthe next step.

Step B: tert-butyl(3R)-3-[[3-amino-4-[(2-methyl-3-pyridyl)amino]thieno[2,3-b]pyridine-2-carbonyl]amino]piperidine-1-carboxylate

To a sealed tube containing2-chloro-4-[(2-methyl-3-pyridyl)amino]pyridine-3-carbonitrile (397 mg,1.62 mmol) was added a 0.5 M solution of tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate22) in dioxane (3.89 mL, 1.95 mmol) and was heated in the sealed tube ina 150° C. oil bath for 15 minutes. The mixture was cooled to rt to givethe title compound, which was used directly in the next reaction.

Step C: (R)-tert-Butyl3-(5-(2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a reaction vial containing of tert-butyl(3R)-3-[[3-amino-4-[(2-methyl-3-pyridyl)amino]thieno[2,3-b]pyridine-2-carbonyl]amino]piperidine-1-carboxylate(783 mg, 1.62 mmol) was added CDI (1.052 g, 6.488 mmol). The reactionvial was sealed and the vessel was evacuated and refilled with argontwice. The mixture was heated for 5 minutes in a 50° C. oil bath underargon, then it was heated at 150° C. for 10 minutes, then the mixturewas cooled to room temperature. The mixture was partitioned betweenEtOAc (50 mL) and water (50 mL). The aqueous phase was extracted withEtOAc (2×50 mL) and the combined organic extracts were washed withsaturated aqueous NaCl (50 mL). The organic phase was dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue waspurified by flash column chromatography to give the title compound as ayellow solid (699.7 mg, 84.82% yield).

Step D:(R)-5-(2-Methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (R)-tert-butyl3-(5-(2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(699.7 mg, 1.376 mmol) in dioxane (5 mL) was added HCl in dioxane (5 mL,4 M, 20 mmol). The suspension was stirred at rt for 30 min. The reactionmixture was filtered, the precipitate washed with dioxane and wasair-dried. The gummy solid was dissolved in a mixture of MeOH and DCMand the resulting solution was concentrated to dryness and dried undervacuum to yield a yellow foamy solid (689.3 mg). Part of the residue(200 mg) was purified by HPLC to give the title compound as a whitepowder (36.9 mg).

Step E:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a suspension of crude(R)-5-(2-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(127 mg, 0.264 mmol) in THF (2.5 mL) was added triethylamine (147 μL,1.06 mmol). To the resulting suspension was added a solution of acryloylchloride in DCM (2.9 mL, 0.10 M, 0.29 mmol). The suspension was stirredat rt for 15 min. The reaction mixture was concentrated to dryness, theresidue dissolved in MeOH, and purified by HPLC to give the titlecompound as a white powder (15.6 mg). MS (ESI): mass calcd. forC₂₃H₂₂N₆O₃S, 462.5; m/z found, 463.2 [M+H]⁺. 1H NMR (400 MHz, MeOH, 1:1mixture of rotamers) δ 8.72-8.77 (m, 1H), 8.38 (d, J=5.56 Hz, 1H),8.16-8.24 (m, 1H), 7.70-7.78 (m, 1H), 6.75-6.86 (m, 1H), 6.21 (dd,J=4.04, 16.67 Hz, 1H), 6.15 (d, J=5.56 Hz, 1H), 5.75 (t, J=9.09 Hz, 1H),4.51-4.59 (m, 0.5H), 4.26-4.35 (m, 0.5H), 4.14-4.21 (m, 0.5H), 3.92-4.06(m, 1.5H), 3.13-3.26 (m, 1H), 2.83-2.99 (m, 1H), 2.03-2.12 (m, 1H),1.83-1.94 (m, 1H), 1.66-1.83 (m, 1H), 1.53-1.66 (m, 1H).

Example 359:(R)-5-(2-Methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the conditions described inExample 358, steps A-D. MS (ESI): mass calcd. for C₂₀H₂₀N₆O₂S, 408.5;m/z found, 409.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.70 (d, J=3.54 Hz,1H), 8.39 (d, J=5.56 Hz, 1H), 8.05 (d, J=8.08 Hz, 1H), 7.65 (dd, J=5.05,8.08 Hz, 1H), 6.13 (d, J=5.56 Hz, 1H), 4.28 (tt, J=3.85, 10.80 Hz, 1H),3.54 (dd, J=4.04, 12.13 Hz, 1H), 3.37 (d, J=12.63 Hz, 1H), 2.87-3.04 (m,2H), 2.47 (s, 3H), 2.00-2.20 (m, 2H), 1.62-1.95 (m, 2H).

Example 360:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3,4-dichlorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 3,4-dichloroaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₃H₁₉Cl₂N₅O₃S, 516.4; m/z found,515.8 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.46 (d, J=6.1 Hz, 1H), 7.83(d, J=8.5 Hz, 1H), 7.78 (s, 1H), 7.47 (d, J=8.6 Hz, 1H), 6.82 (dd,J=16.7, 10.6 Hz, 1H), 6.40 (s, 1H), 6.23 (dd, J=16.5, 7.4 Hz, 1H),5.79-5.74 (m, 1H), 4.59-4.24 (m, 1H), 4.21-3.94 (m, 2H), 3.26-3.14 (m,1H), 2.98-2.88 (m, 1H), 2.12-2.09 (m, 1H), 1.92-1.89 (m, 1H), 1.78 (brs,1H), 1.63 (brs, 1H).

Example 361:(R)-5-Isopropyl-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using propan-2-amine in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₁₇H₂₁N₅O₂S, 359.4; m/z found, 360.1[M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.28 (s, 1H), 9.11 (s,1H), 8.50 (d, J=5.8 Hz, 1H), 8.29 (d, J=7.5 Hz, 1H), 7.17 (d, J=5.9 Hz,1H), 4.76 (s, 1H), 4.25-4.11 (m, 1H), 3.33-3.23 (m, 1H), 3.19-3.16 (m,1H), 2.95-2.74 (m, 2H), 1.91-1.88 (m, 2H), 1.79-1.57 (m, 2H), 1.48 (d,J=6.9 Hz, 6H).

Example 362:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 4-chloro-3-(trifluoromethyl)aniline in placeof 2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₄H₁₉ClF₃N₅O₃S, 550.0; m/z found,549.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.29 (d, J=15.3 Hz, 1H),8.35 (d, J=5.5 Hz, 1H), 8.14-8.10 (m, 2H), 8.01 (d, J=8.5 Hz, 1H), 7.88(dd, J=8.5, 2.3 Hz, 1H), 6.87-6.72 (m, 1H), 6.18 (d, J=5.5 Hz, 1H), 6.12(d, J=16.5 Hz, 1H), 5.69 (dd, J=10.5, 2.3 Hz, 1H), 4.53-4.17 (m, 1H),4.11-3.98 (m, 1H), 3.19-2.94 (m, 2H), 2.85-2.62 (m, 1H), 2.01-1.91 (m,1H), 1.86-1.59 (m, 2H), 1.44 (s, 1H).

Example 363:(R)—N-(1-(3-Methoxy-3-methylbutanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 3-Methoxy-3-methylbutanoic acid

To a cold solution of sodium hypobromite [prepared from NaOH (1.6 g, 40mmol), bromine (3.2 g, 20 mmol), and water (6 g)] was added withstirring 4-methoxy-4-methylpentan-2-one (650 mg, 5.0 mmol), keeping thetemperature below 20° C. After the addition of the ketone was complete,the reaction mixture was stirred an additional 3 h, the bromoform layerwas removed and the aqueous layer washed repeatedly with dilute sulfuricacid, and sodium bisulfite was added to destroy excess bromine. The acidwas isolated by ether extraction, washed with brine, and dried overanhydrous MgSO₄, filtered, and concentrated to dryness to give the titlecompound as a yellow oil (201 mg).

Step B:(R)—N-(1-(3-Methoxy-3-methylbutanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.28 mmol), 3-methoxy-3-methylbutanoic acid (45mg, 0.34 mmol), HATU (138 mg, 0.363 mmol), and triethylamine (0.156 mL,1.12 mmol) in DMF (3 mL) was stirred at rt overnight, then purified byflash column chromatography and preparative TLC to give the titlecompound as a white solid (80 mg, 46% yield). MS (ESI): mass calcd. forC₃₃H₃₅N₅O₅S, 613.7; m/z found, 614.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.37-8.29 (m, 1H), 7.46-7.36 (m, 2H), 7.34-7.27 (m, 1H), 7.21-7.13 (m,1H), 7.13-7.03 (m, 3H), 7.01-6.94 (m, 1H), 6.15-6.00 (m, 1H), 4.45-4.32(m, 1H), 4.26-3.91 (m, 2H), 3.23 (s, 3H), 3.18-3.03 (m, 1H), 2.96-2.68(m, 1H), 2.66-2.58 (m, 2H), 2.12 (s, 3H), 2.08-1.98 (m, 1H), 1.88-1.79(m, 1H), 1.72-1.47 (m, 2H), 1.34-1.24 (m, 6H).

Example 364:(R,Z)—N-(1-(3-Acetamidoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 200 mg, 0.4 mmol), (Z)-3-acetamidoprop-2-enoic acid(Intermediate 33, 129 mg, 1.00 mmol), triethylamine (101 mg, 1.00 mmol),and HATU (380 mg, 1.0 mmol) in DMF (3 mL) was stirred at rt for 3 h.Water was added and the precipitate was collected by filtration. Theresidue was purified by flash column chromatography to give the titlecompound as a yellow solid (13 mg, 5.2% yield). MS (ESI): mass calcd.for C₃₂H₃₀N₆O₅S, 610.7; m/z found, 611.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.32 (d, J=5.5 Hz, 1H), 7.46-7.27 (m, 4H), 7.21-7.13 (m, 1H),7.14-7.03 (m, 3H), 7.02-6.94 (m, 1H), 6.07 (d, J=5.5 Hz, 1H), 5.64 (d,J=8.8 Hz, 1H), 4.51-4.33 (m, 1H), 4.16-3.88 (m, 3H), 3.15-2.94 (m, 1H),2.16-2.02 (m, 7H), 1.93-1.84 (m, 1H), 1.82-1.71 (m, 1H), 1.63-1.54 (m,1H).

Example 365:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 300, 60 mg, 0.12 mmol), (E)-2-cyano-3-cyclopropylprop-2-enoicacid (Intermediate 17) (23 mg, 0.17 mmol), HATU (55 mg, 0.15 mmol), andtriethylamine (0.062 mL 0.45 mmol) in DMF (2 mL) was stirred at rtovernight. The reaction mixture was purified by flash columnchromatography and preparative TLC to give the title compound as ayellow solid (13 mg, 18% yield). MS (ESI): mass calcd. for C₃₄H₃₀N₆O₄S,618.7; m/z found, 619.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34 (d,J=5.5 Hz, 1H), 7.45-7.35 (m, 2H), 7.33-7.26 (m, 1H), 7.21-7.14 (m, 1H),7.13-7.03 (m, 3H), 7.00-6.95 (m, 1H), 6.61-6.49 (m, 1H), 6.08 (d, J=5.6Hz, 1H), 4.61-4.51 (m, 2H), 4.10-3.96 (m, 2H), 3.20-3.16 (m, 1H), 2.13(s, 3H), 2.10-1.96 (m, 2H), 1.94-1.85 (m, 1H), 1.80-1.59 (m, 2H),1.26-1.15 (m, 2H), 1.02-0.82 (m, 2H).

Example 366:(R)—N-(1-(2-Chloroacryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98, 50 mg, 0.09 mmol), 2-chloroprop-2-enoic acid (20 mg, 0.19mmol), HATU (46 mg, 0.12 mmol), and diisopropylethylamine (30 mg, 0.23mmol) in DMF (5 mL) was stirred at rt for 2 h. The mixture was purifiedby flash column chromatography, and by preparative TLC to give the titlecompound as a white solid (10 mg, 18% yield). MS (ESI): mass calcd. forC₃₀H₂₆ClN₅O₄S, 588.1; m/z found, 588.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):δ 8.36-8.30 (m, 1H), 7.44-7.37 (m, 2H), 7.33-7.27 (m, 1H), 7.21-7.14 (m,1H), 7.12-7.03 (m, 3H), 7.01-6.95 (m, 1H), 6.11-6.05 (m, 1H), 5.72 (m,2H), 4.45-3.88 (m, 3H), 3.25-2.90 (m, 2H), 2.17-2.02 (m, 4H), 1.95-1.84(m, 1H), 1.81-1.69 (m, 1H), 1.66-1.57 (m, 1H).

Example 367:(R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R,E)-tert-Butyl(4-(3-(5-(*R)-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate

A solution of(R)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 300, 60 mg, 0.11 mmol),(E)-4-(tert-butoxycarbonylamino)but-2-enoic acid (Intermediate 12, 45mg, 0.22 mmol), HATU (56 mg, 0.15 mmol), and diisopropylethylamine (36mg, 0.28 mmol) in DMF (5 mL) was stirred at rt for 2 h. The mixture waspurified by flash column chromatography, then by preparative TLC to givethe title compound as a white solid (43 mg, 56% yield).

Step B:(R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added (R,E)-tert-butyl(4-(3-(5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate(43 mg, 0.063 mmol), concentrated HCl (5 mL), and MeOH (5 mL) and wasstirred at rt for 1 h. The mixture was concentrated to dryness and waspurified by flash column chromatography to give the title compound as awhite solid (19 mg, 48% yield). MS (ESI): mass calcd. for C₃₁H₃₀N₆O₄S,582.7; m/z found, 583.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.38-8.32 (m,1H), 7.45-7.37 (m, 2H), 7.32-7.26 (m, 1H), 7.21-7.14 (m, 1H), 7.13-7.03(m, 3H), 7.02-6.94 (m, 1H), 6.86-6.78 (m, 1H), 6.77-6.67 (m, 1H),6.13-6.06 (m, 1H), 4.45-3.90 (m, 3H), 3.80-3.70 (m, 2H), 3.23-3.07 (m,1H), 2.91-2.80 (m, 1H), 2.16-2.02 (m, 4H), 1.94-1.84 (m, 1H), 1.81-1.69(m, 1H), 1.65-1.52 (m, 1H).

Example 368:(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R,E)-tert-Butyl(4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidin-1-yl)-4-oxobut-2-en-1-yl)carbamate

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 159, 300 mg, 0.58 mmol),(E)-4-(tert-butoxycarbonylamino)but-2-enoic acid (Intermediate 12, 231mg, 1.15 mmol), HATU (284 mg, 0.747 mmol), and DIEA (186 mg, 1.44 mmol)in DMF (6 mL) was stirred at rt for 2 h. The mixture was purified byflash column chromatography using two different methods to give thetitle compound as a white solid (265 mg, 68.9% yield).

Step B:(R,E)-N-(1-(4-Aminobut-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added (R,E)-tert-butyl(4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidin-1-yl)-4-oxobut-2-en-1-yl)carbamate(265 mg, 0.396 mmol), concentrated HCl (8 mL), and MeOH (8 mL) and wasstirred at rt for 1 h. The mixture was concentrated to dryness andpurified by flash column chromatography to give the title compound aswhite solid (188 mg, 75.5% yield).

Step C:(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R,E)-N-(1-(4-aminobut-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(135 mg, 0.220 mmol), formaldehyde (0.2 mL, 37 wt. % in H₂O), andNaBH(OAc)₃ (93 mg, 0.44 mmol) in DCM (8 mL) was stirred at rt for 5 h.The mixture was concentrated to dryness and purified by flash columnchromatography to give the title compound as a white solid (63 mg, 43%yield). MS (ESI): mass calcd. for C₃₂H₃₂N₆O₄S, 596.7; m/z found, 597.3[M+H]⁺. 1H NMR (400 MHz, CD3OD): δ 8.45 (s, 1H), 8.37-8.32 (m, 1H),7.44-7.36 (m, 2H), 7.32-7.26 (m, 1H), 7.21-7.14 (m, 1H), 7.12-7.03 (m,3H), 7.01-6.95 (m, 1H), 6.84-6.74 (m, 1H), 6.68-6.56 (m, 1H), 6.11-6.05(m, 1H), 4.09-3.69 (m, 4H), 3.64-3.58 (m, 2H), 3.56-3.44 (m, 1H), 2.63(s, 6H), 2.40-2.15 (m, 2H), 2.12 (s, 3H)

Example 369:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(vinylsulfonyl)pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-I in Example 1, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G and usingethenesulfonyl chloride in place of prop-2-enoyl chloride in step I toyield the title compound. MS (ESI): mass calcd. for C₂₈H₂₅N₅O₅S₂, 575.7;m/z found, 576.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d, J=5.5 Hz,1H), 7.45-7.35 (m, 2H), 7.34-7.25 (m, 1H), 7.21-7.13 (m, 1H), 7.12-7.03(m, 3H), 6.99-6.93 (m, 1H), 6.80-6.64 (m, 1H), 6.21 (d, J=16.5 Hz, 1H),6.14-6.03 (m, 2H), 4.61-4.45 (m, 1H), 3.66-3.55 (m, 1H), 3.53-3.45 (m,1H), 3.38-3.31 (m, 1H), 3.29-3.20 (m, 1H), 2.32-2.20 (m, 1H), 2.12 (s,3H), 2.08-2.00 (m, 1H).

Example 370:(R)-5-(2-Methyl-4-phenoxyphenl)-N-(1-trideuteriomethylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 100 mg, 0.19 mmol) and deuterated-formaldehyde (12 mg,0.38 mmol, 37 wt. % in H₂O) were added to MeOH (3 mL). After stirring atrt for 5 min, sodium cyanoborodeuteride (36 mg, 0.55 mmol) was added.The mixture was stirred at rt for 2 h. The reaction was concentrated todryness and the residue was purified by flash column chromatography togive the title compound as a yellow solid (38 mg, 37% yield). MS (ESI):mass calcd. for C₂₈H₂₄D₃N₅O₃S, 516.6; m/z found, 517.2 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.26 (d, J=4.9 Hz, 1H), 7.46-7.33 (m, 2H), 7.31-7.24(m, 1H), 7.19-7.11 (m, 1H), 7.11-7.01 (m, 3H), 7.00-6.90 (m, 1H), 6.00(d, J=5.1 Hz, 1H), 4.20-4.06 (m, 1H), 2.99-2.88 (m, 1H), 2.75-2.61 (m,1H), 2.25-2.02 (m, 5H), 1.92-1.75 (m, 2H), 1.71-1.61 (m, 1H), 1.54-1.44(m, 1H).

Example 371:(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 250 mg, 0.45 mmol),(E)-4-[tert-butoxycarbonyl(methyl)amino]but-2-enoic acid (Intermediate10, 200 mg, 0.93 mmol), HATU (230 mg, 0.61 mmol), and DIEA (150 mg, 1.17mmol) in DMF (6 mL) was stirred at rt for 2 h. The mixture was purifiedby HPLC and by flash column chromatography to give the title compound asa white solid (228 mg, 70.2% yield).

Step F:(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R,E)-tert-butylmethyl(4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate(228 mg, 0.327 mmol), concentrated HCl (5 mL), and MeOH (5 mL) wasstirred at rt for 1 h under N2. The mixture was concentrated to drynessand purified by flash column chromatography to give the title compoundas a white solid (120 mg, 57% yield).

Step G:(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R,E)-5-(2-methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(68 mg, 0.11 mmol), formaldehyde (0.5 mL, 37 wt. % in H₂O), andNaBH(OAc)₃ (45 mg, 0.21 mmol) in DCM (8 mL) was stirred at rt for 5 h.The mixture was concentrated to dryness and purified by flash columnchromatography to give the title compound as a white solid (37 mg, 52%yield). MS (ESI): mass calcd. for C₃₃H₃₄N₆O₄S, 610.7; m/z found, 611.3[M+H]⁺. 1H NMR (400 MHz, CD3OD): δ 8.41 (s, 1H), 8.37-8.30 (m, 1H),7.45-7.36 (m, 2H), 7.34-7.26 (m, 1H), 7.21-7.14 (m, 1H), 7.12-7.03 (m,3H), 7.01-6.95 (m, 1H), 6.93-6.86 (m, 1H), 6.75-6.64 (m, 1H), 6.11-6.05(m, 1H), 4.54-4.50 (m, 1H), 4.42-3.89 (m, 3H), 3.83-3.73 (m, 2H),3.25-3.14 (m, 1H), 2.97-2.87 (m, 1H), 2.76 (s, 6H), 2.16-2.02 (m, 4H),1.94-1.82 (m, 1H), 1.82-1.70 (m, 1H), 1.66-1.53 (m, 1H)

Example 372:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(vinylsulfonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-I in Example 1, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G and usingethenesulfonyl chloride in place of prop-2-enoyl chloride in step I toyield the title compound. MS (ESI): mass calcd. for C₂₉H₂₇N₅O₅S₂, 589.7;m/z found, 590.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d, J=5.6 Hz,1H), 7.44-7.35 (m, 2H), 7.30 (d, J=8.6 Hz, 1H), 7.21-7.13 (m, 1H),7.11-7.03 (m, 3H), 7.01-6.92 (m, 1H), 6.72-6.60 (m, 1H), 6.22-6.04 (m,3H), 4.16-3.98 (m, 1H), 3.84-3.69 (m, 1H), 3.63-3.47 (m, 1H), 2.81-2.55(m, 2H), 2.12 (s, 3H), 2.04-1.95 (m, 1H), 1.93-1.83 (m, 1H), 1.77-1.63(m, 1H), 1.62-1.50 (m, 1H).

Example 373:(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To an oven dried microwave vial with a stir bar under Ar were added(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860, 62 mg, 0.10 mmol), trans-4-dimethylaminocrotonic acidhydrochloride (37.6 mg, 0.227 mmol), HATU (202 mg, 0.531 mmol), THF (3.0mL), and triethylamine (0.20 mL, 1.4 mmol). The reaction vial was cappedand allowed to warm in the microwave for 5 min at 100° C. The reactionmixture was concentrated to dryness, filtered, and purified by HPLC togive the title compound (27 mg, 44% yield). MS (ESI): mass calcd. forC₃₂H₃₂N₆O₄S, 596.7; m/z found, 597.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.39-8.21 (m, 1H), 7.45-7.33 (m, 4H), 7.25-7.06 (m, 5H), 6.83-6.57 (m,2H), 6.24-6.08 (m, 1H), 4.57-3.87 (m, 3H), 3.27-2.83 (m, 4H), 2.36-2.20(m, 6H), 2.12-1.46 (m, 4H).

Example 374:(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylsulfonyl)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylthio)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (E)-4-methylsulfanylbut-2-enoic acid (Intermediate 37,0.556 g, 4.201 mmol), HATU (1.0 g, 2.6 mmol), and triethylamine (1.0 g,9.9 mmol) in DMF (10 mL) was added(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 0.75 g, 1.5 mmol) and was stirred at rt for 4 hours. Themixture was purified by flash column chromatography to give the titlecompound (300 mg, 33% yield).

Step B:(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylsulfonyl)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a mixture of(R,E)-5-(2-methyl-4-phenoxyphenyl)-N-(1-(4-(methylthio)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(300 mg, 0.49 mmol) in DCM (10 mL) was added3-chlorobenzenecarboperoxoic acid (169 mg, 0.735 mmol) and was stirredat rt for 4 hours. The mixture was dispersed between DCM and a 1 Maqueous Na₂CO₃ solution. The organic layer was collected, concentratedto dryness, and purified by flash column chromatography, then bypreparative TLC to give the title compound (58 mg, 17% yield). MS (ESI):mass calcd. for C₃₂H₃₁N₅O₆S₂, 645.7; m/z found, 646.2 [M+H]⁺. 1H NMR(400 MHz, DMSO-d6): δ 8.60-8.26 (m, 1H), 8.25-8.10 (m, 1H), 7.45-7.39(m, 2H), 7.29-7.20 (m, 1H), 7.19-7.15 (m, 1H), 7.12-7.07 (m, 2H),7.06-7.02 (m, 1H), 6.96-6.91 (m, 1H), 6.89-6.78 (m, 1H), 6.59-6.48 (m,1H), 5.88-5.69 (m, 1H), 4.45-4.12 (m, 1H), 4.11-4.04 (m, 2H), 4.01-3.85(m, 1H), 3.82-3.75 (m, 1H), 3.13-3.02 (m, 1H), 2.96-2.90 (m, 3H),2.86-2.63 (m, 1H), 2.02 (s, 3H), 1.97-1.93 (m, 1H), 1.81-1.72 (m, 1H),1.67-1.56 (m, 1H), 1.49-1.39 (m, 1H).

Example 375:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-I in Example 1, and using2,3,4,5,6-pentadeuteriophenol in place of phenol in step A and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G to yield thetitle compound. MS (ESI): mass calcd. for C₃₀H₂₂D₅N₅O₄S, 558.7; m/zfound, 559.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35-8.30 (m, 1H),7.32-7.27 (m, 1H), 7.07-7.03 (m, 1H), 7.00-6.94 (m, 1H), 6.85-6.72 (m,1H), 6.24-6.14 (m, 1H), 6.09-6.05 (m, 1H), 5.76-5.68 (m, 1H), 4.56-3.89(m, 3H), 3.26-2.82 (m, 2H), 2.15-2.00 (m, 4H), 1.92-1.81 (m, 1H),1.78-1.66 (m, 1H), 1.63-1.52 (m, 1H).

Example 376:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G in Example 1, and using2,3,4,5,6-pentadeuteriophenol in place of phenol in step A and using1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (intermediate 5) in placeof tert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in stepG to yield the title compound. MS (ESI): mass calcd. for C₂₉H₂₀D₅N₅O₄S,544.6; m/z found, 545.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.30-10.19(m, 1H), 8.41-8.29 (m, 2H), 7.43-7.35 (m, 1H), 7.13-7.07 (m, 1H),7.04-6.94 (m, 1H), 6.69-6.49 (m, 1H), 6.21-6.08 (m, 1H), 6.05-5.95 (m,1H), 5.75-5.63 (m, 1H), 4.59-4.41 (m, 1H), 3.96-3.45 (m, 4H), 2.27-1.92(m, 5H).

Example 377:(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,58-triazaacenaphthylene-2-carboxamide

Step A: (R,E)-tert-Butylmethyl(4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidin-1-yl)-4-oxobut-2-en-1-yl)carbamate

A solution of (E)-4-[tert-butoxycarbonyl(methyl)amino]but-2-enoic acid(Intermediate 10, 165 mg, 0.766 mmol),(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 159, 200 mg, 0.38 mmol), HATU (112 mg, 0.295 mmol), and DIEA(247 mg, 1.92 mmol) in DMF (5 mL) was stirred at rt for 1 h. The mixturewas purified by flash column chromatography using two different methodsto give the title compound as a light yellow solid (93 mg, 36% yield).

Step B:(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added (R,E)-tert-butylmethyl(4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidin-1-yl)-4-oxobut-2-en-1-yl)carbamate(93 mg, 0.14 mmol), concentrated HCl (5 mL), and MeOH (5 mL) and wasstirred at rt for 1 h. The mixture was concentrated to dryness and theresidue was purified by flash column chromatography to give the titlecompound as a white solid (48 mg, 60% yield). MS (ESI): mass calcd. forC₃₁H₃₀N₆O₄S, 582.7; m/z found, 583.2 [M+H]⁺. 1H NMR (400 MHz, CD3OD): δ8.35-8.31 (m, 1H), 7.44-7.37 (m, 2H), 7.32-7.26 (m, 1H), 7.20-7.15 (m,1H), 7.12-7.04 (m, 3H), 7.00-6.95 (m, 1H), 6.82-6.58 (m, 2H), 6.10-6.06(m, 1H), 4.16-3.42 (m, 7H), 2.72-2.66 (m, 3H), 2.43-2.03 (m, 5H)

Example 378:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenox)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 41, 150 mg, 0.28 mmol),(E)-2-cyano-3-cyclopropyl-prop-2-enoic acid (Intermediate 17) (76 mg,0.55 mmol), HATU (137 mg, 0.360 mmol), and DIEA (107 mg, 0.831 mmol) inDMF (5 mL) was stirred at room temperature for 1 h. Then the reactionmixture was purified by normal phase flash column chromatography (SiO₂)using two different methods to give the title compound as a white solid(71 mg, 41% yield). MS (ESI): mass calcd. for C₃₄H₂₅D₅N₆O₄S, 623.7; m/zfound, 624.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35-8.30 (m, 1H),7.32-7.27 (m, 1H), 7.07-7.03 (m, 1H), 7.00-6.95 (m, 1H), 6.57-6.50 (m,1H), 6.10-6.05 (m, 1H), 4.08-3.93 (m, 2H), 3.67-3.62 (m, 2H), 3.22-3.10(m, 1H), 2.12 (s, 3H), 2.10-1.95 (m, 2H), 1.93-1.84 (m, 1H), 1.80-1.68(m, 1H), 1.68-1.56 (m, 1H), 1.25-1.16 (m, 2H), 1.01-0.93 (m, 1H),0.90-0.78 (m, 1H).

Example 379:(R)—N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-I in Example 1, and using2,3,4,5,6-pentadeuteriophenol in place of phenol in step A and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G and usingcarbononitridic bromide in place of prop-2-enoyl chloride in step I toyield the title compound. MS (ESI): mass calcd. for C₂₈H₁₉D₅N₆O₃S,529.6; m/z found, 530.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35-8.31 (m,1H), 7.32-7.27 (m, 1H), 7.07-7.03 (m, 1H), 7.00-6.94 (m, 1H), 6.09-6.04(m, 1H), 4.16-4.07 (m, 1H), 3.61-3.52 (m, 1H), 3.40-3.30 (m, 1H),3.10-2.94 (m, 2H), 2.12 (s, 3H), 2.07-1.98 (m, 1H), 1.90-1.81 (m, 1H),1.81-1.70 (m, 1H), 1.66-1.54 (m, 1H).

Example 380:(R)-5-(2-Methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-N-(1-(trideuteriomethyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 41, 155 mg. 0.286 mmol) and deuterated-formaldehyde (18mg, 0.56 mmol, 37 wt. % in H₂O) in MeOH (4 mL) was stirred at rt for 30min, then sodium cyanoborodeuteride (57 mg, 0.86 mmol) was added. Thereaction mixture was stirred at rt overnight. The reaction wasconcentrated to dryness and the residue was purified by flash columnchromatography to give the title compound as a yellow solid (66 mg, 43%yield). MS (ESI): mass calcd. for C₂₈H₁₉D₈N₅O₃S, 521.7; m/z found, 522.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.39-8.15 (m, 1H), 7.38-7.19 (m, 1H),7.11-6.88 (m, 2H), 6.16-5.88 (m, 1H), 4.24-4.06 (m, 1H), 3.01-2.82 (s,1H), 2.78-2.61 (m, 1H), 2.32-2.01 (m, 5H), 1.93-1.76 (m, 2H), 1.72-1.59(m, 1H), 1.55-1.42 (m, 1H).

Example 381:(R)-5-(2-Methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution(R)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 41, 150 mg, 0.28 mmol), aqueous formaldehyde (1 mL, 37 wt.% in H₂O), and NaBH(OAc)₃ (117 mg, 0.554 mmol) in DCM (10 mL) wasstirred at rt for 5 h. The mixture was concentrated to dryness andpurified by flash column chromatography to give the title compound as alight yellow solid (90 mg, 57% yield). MS (ESI): mass calcd. forC₂₈H₂₂D₅N₅O₃S, 518.6; m/z found, 519.2 [M+H]⁺. 1H NMR (400 MHz, CD₃OD):δ 8.35-8.28 (m, 1H), 7.33-7.27 (m, 1H), 7.07-7.03 (m, 1H), 7.01-6.94 (m,1H), 6.09-6.04 (m, 1H), 4.34-4.22 (m, 1H), 3.48-3.37 (m, 1H), 3.27-3.18(m, 1H), 2.88-2.71 (m, 5H), 2.11 (s, 3H), 2.07-1.96 (m, 2H), 1.90-1.76(m, 1H), 1.74-1.59 (m, 1H)

Example 382:(R,E)-N-(1-(4-Aminobut-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 368, steps A-B. MS (ESI): mass calcd. for C₃₀H₂₈N₆O₄S, 568.6;m/z found, 569.3 [M+H]⁺. 1H NMR (400 MHz, CD₃OD): δ 8.42 (s, 1H),8.37-8.32 (m, 1H), 7.44-7.36 (m, 2H), 7.32-7.26 (m, 1H), 7.21-7.14 (m,1H), 7.12-7.03 (m, 3H), 7.01-6.95 (m, 1H), 6.84-6.74 (m, 1H), 6.68-6.56(m, 1H), 6.11-6.05 (m, 1H), 4.08-3.44 (m, 7H), 2.44-2.13 (m, 2H), 2.12(s, 3H)

Example 383:(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylsulfonamido)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R,E)-N-(1-(4-aminobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 27, 300 mg, 0.52 mmol) and triethylamine (104 mg, 1.03 mmol) inDCM (5 mL) was added ClSO₂Me (59 mg, 0.52 mmol) and was stirred at roomtemperature for 15 minutes. The mixture was dispersed between DCM andwater and the organic layer was collected, concentrated to dryness, andpurified by flash column chromatography, then by preparative TLC to givethe title compound (52 mg, 15% yield). MS (ESI): mass calcd. forC₃₂H₃₂N₆O₆S₂, 660.8; m/z found, 661.2 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6):δ 8.54-8.26 (m, 1H), 8.26-8.13 (m, 1H), 7.47-7.38 (m, 2H), 7.36-7.21 (m,2H), 7.20-7.14 (m, 1H), 7.13-7.07 (m, 2H), 7.07-7.03 (m, 1H), 6.97-6.91(m, 1H), 6.66-6.53 (m, 2H), 5.90-5.73 (m, 1H), 4.45-4.07 (m, 1H),4.04-3.87 (m, 1H), 3.82-3.71 (m, 3H), 3.15-2.99 (m, 1H), 2.88 (s, 3H),2.85-2.61 (m, 1H), 2.03 (s, 3H), 1.97-1.90 (m, 1H), 1.82-1.70 (m, 1H),1.69-1.55 (m, 1H), 1.47-1.35 (m, 1H).

Example 384:(R)—N-(1-(2-(Dimethylamino)acetyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 159, 150 mg, 0.29 mmol), 2-(dimethylamino)acetic acid (59 mg,0.57 mmol), HATU (142 mg, 0.373 mmol), and DIEA (111 mg, 0.861 mmol) inDMF (5 mL) and was stirred at rt for 1 h. The mixture was purified byflash column chromatography to give the title compound as a white solid(130 mg, 74% yield). MS (ESI): mass calcd. for C₃₀H₃₀N₆O₄S, 570.7; m/zfound, 571.3 [M+H]⁺. 1H NMR (400 MHz, CD3OD): δ 8.35-8.30 (m, 1H),7.43-7.37 (m, 2H), 7.32-7.28 (m, 1H), 7.20-7.14 (m, 1H), 7.11-7.04 (m,3H), 7.00-6.94 (m, 1H), 6.10-6.04 (m, 1H), 4.67-4.57 (m, 1H), 4.03-3.96(m, 2H), 3.91-3.81 (m, 1H), 3.74-3.62 (m, 1H), 3.60-3.41 (m, 2H),2.88-2.84 (m, 6H), 2.39-2.14 (m, 2H), 2.11 (s, 3H).

Example 385:(R,E)-N-(1-(2-Cyanobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874) (300 mg, 0.53 mmol), acetaldehyde (116 mg, 2.65 mmol),piperidine (0.1 ml), and EtOH (10 mL) and was stirred at rt for 0.5 h.The mixture was diluted with DCM, washed with 1 N HCl and saturatedaqueous NaHCO₃, dried over anhydrous Na₂SO₄, concentrated to dryness,and purified by flash column chromatography to give the title compoundas a yellow solid (46 mg, 15% yield). MS (ESI): mass calcd. forC₃₂H₂₈N₆O₄S, 592.7; m/z found, 593.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 10.18 (s, 1H), 8.35-8.31 (m, 1H), 8.14-8.02 (m, 1H), 7.47-7.40 (m,2H), 7.39-7.33 (m, 1H), 7.22-7.15 (m, 1H), 7.13-7.03 (m, 4H), 6.99-6.93(m, 1H), 5.99-5.94 (m, 1H), 3.89-3.78 (m, 1H), 3.18-2.82 (m, 4H),2.09-2.00 (m, 6H), 1.97-1.89 (m, 1H), 1.83-1.74 (m, 1H), 1.73-1.61 (m,1H), 1.54-1.43 (m, 1H).

Example 386:N—((R)-1-((S)-Azetidine-2-carbonyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (S)-tert-butyl2-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carbonyl)azetidine-1-carboxylate

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 100 mg, 0.19 mmol),(2S)-1-tert-butoxycarbonylazetidine-2-carboxylic acid (63 mg, 0.28mmol), HATU (107 mg, 0.281 mmol), and triethylamine (0.104 mL, 0.748mmol) in DMF (3 mL) was stirred at rt overnight. The reaction mixturewas purified by flash column chromatography to give the title compoundas a white solid (115 mg, 90.0% yield).

Step B:N—((R)-1-((S)-Azetidine-2-carbonyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (S)-tert-butyl2-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carbonyl)azetidine-1-carboxylate(115 mg, 0.168 mmol) in 2 N HCl in MeOH (2 mL) was stirred at rt for 4h, then concentrated to dryness. The residue was adjusted with 2 NNaHCO₃ to pH>7, then purified by flash column chromatography to give thetitle compound as a yellow solid (77 mg, 75% yield). MS (ESI): masscalcd. for C₃₁H₃₀N₆O₄S, 582.7; m/z found, 583.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆ and CD₃OD): δ 8.06-8.02 (m, 1H), 7.40-7.26 (m, 2H), 7.16-7.06(m, 2H), 7.05-6.99 (m, 2H), 6.98-6.92 (m, 1H), 6.92-6.83 (m, 1H), 5.72(d, J=5.5 Hz, 1H), 5.08-4.51 (m, 1H), 3.98-3.81 (m, 1H), 3.66-3.58 (m,1H), 3.58-3.43 (m, 2H), 3.43-3.32 (m, 1H), 3.18-3.09 (m, 2H), 2.81-2.56(m, 1H), 2.48-2.34 (m, 1H), 2.01 (s, 3H), 1.92-1.80 (m, 2H), 1.77-1.66(m, 1H), 1.54-1.42 (m, 1H).

Example 387:(R,E)-N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 300, 100 mg, 0.19 mmol), 2-cyanoacetic acid (32 mg, 0.37 mmol),HATU (92 mg, 0.24 mmol), and DIEA (60 mg, 0.47 mmol) in DMF (5 mL) wasstirred at rt for 2 h. The reaction mixture was purified by flash columnchromatography to give the title compound as a white solid (82 mg, 78%yield).

Step B:(R,E)-N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.18 mmol), 3-methyloxetane-3-carbaldehyde (53 mg, 0.53 mmol),piperidine (0.3 mL), AcOH (0.1 mL), 4A molecular sieves (0.5 g), anddioxane (10 mL) and was stirred at 100° C. for 1 h under N2. The mixturewas concentrated to dryness and purified by flash column chromatographyto give the title compound as a white solid (71 mg). MS (ESI): masscalcd. for C₃₅H₃₂N₆O₅S, 648.7; m/z found, 649.3 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.33-8.28 (m, 1H), 7.42-7.35 (m, 2H), 7.31-7.23 (m, 2H),7.19-7.12 (m, 1H), 7.11-7.01 (m, 3H), 6.98-6.92 (m, 1H), 6.07-6.02 (m,1H), 5.04-6.91 (m, 1H), 4.73-4.26 (m, 4H), 4.06-3.86 (m, 2H), 3.56-2.76(m, 2H), 2.16-2.01 (m, 4H), 1.97-1.85 (m, 1H), 1.82-1.57 (m, 5H).

Example 388:(R,Z)—N-(1-(2-Fluoro-4-(methylamino)but-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R,Z)-tert-Butyl(3-fluoro-4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)(methyl)carbamate

A solution of(Z)-4-[tert-butoxycarbonyl(methyl)amino]-2-fluoro-but-2-enoic acid(Intermediate 38, 500 mg, 2.1 mmol), HBTU and triethylamine (236 mg,2.33 mmol) in anhydrous DMF (5 mL) was stirred at room temperature for10 min, then(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 250 mg, 0.47 mmol) was added and the mixture was stirredfor 2 h. The crude mixture was purified by flash column chromatographyto give the title compound as a slight yellow solid (21 mg, 6.2% yield).

Step B:(R,Z)—N-(1-(2-Fluoro-4-(methylamino)but-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R,Z)-tert-butyl(3-fluoro-4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)(methyl)carbamate(21 mg, 0.029 mmol) in 6 N HCl in MeOH (10 mL) was concentrated todryness at 50° C. under vacuum to yield a yellow solid. The residue waspurified by flash column chromatography to give the title compound as ayellow solid (15 mg, 76% yield). MS (ESI): mass calcd. for C₃₂H₃₁FN₆O₄S,614.7; m/z found, 615.2 [M+H]⁺. 1H NMR (400 MHz, CD3OD): δ 8.43 (s, 1H),8.34 (d, J=3.6 Hz, 1H), 7.49-7.35 (m, 2H), 7.34-7.25 (m, 1H), 7.23-7.14(m, 1H), 7.13-7.03 (m, 3H), 7.01-6.92 (m, 1H), 6.08 (d, J=5.4 Hz, 1H),5.92-5.75 (m, 1H), 4.54-3.91 (m, 3H), 3.85-3.63 (m, 2H), 3.27-3.11 (m,1H), 3.05-2.88 (m, 1H), 2.77-2.67 (m, 3H), 2.12 (s, 3H), 2.10-2.03 (m,1H), 1.98-1.86 (m, 1H), 1.83-1.56 (m, 2H).

Example 389:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(2-(pyrrolidin-1-yl)acetyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)—N-(1-(2-chloroacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 396, 150 mg, 0.26 mmol) in DCM and triethylamine was addedpyrrolidine (38 mg, 0.53 mmol) in DCM dropwise and was stirred at rt for2 h. The reaction mixture was concentrated to dryness and purified byflash column chromatography, then preparative TLC to give the titlecompound as a yellow solid (68 mg). MS (ESI): mass calcd. forC₃₃H₃₄N₆O₄S, 610.7; m/z found, 611.2 [M+H]⁺. 1H NMR (400 MHz, CDCl3): δ8.33 (d, J=4.7 Hz, 1H), 7.44-7.34 (m, 2H), 7.21-7.12 (m, 2H), 7.12-7.06(m, 2H), 7.03-6.97 (m, 1H), 6.97-6.91 (m, 1H), 5.98 (d, J=4.7 Hz, 1H),4.22-4.03 (m, 1H), 3.94-3.75 (m, 1H), 3.69-3.61 (m, 1H), 3.56-3.37 (m,3H), 3.34-3.19 (m, 1H), 2.73-2.53 (m, 4H), 2.14-2.09 (m, 3H), 1.99-1.89(m, 2H), 1.83-1.73 (m, 6H).

Example 390:(R)-2-(((1-Acryloylpiperidin-3-yl)amino)methyl)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

Step A:N-Methoxy-N-methyl-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using N-methoxymethanamine in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G to yield thetitle compound.

Step B:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbaldehyde

To a solution ofN-methoxy-N-methyl-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(1.7 g, 3.7 mmol) in anhydrous THF (30 mL) was added LiAlH₄ (210 mg, 5.5mmol) and was stirred at rt for 72 h under N2. Next, an aqueous solutionof 1 N KHSO₄ was added cautiously via an addition funnel, and then waterwas added followed by EtOAc. The organic layer was collected and washedwith 1 N HCl, which caused a yellow solid to precipitate, which wascollected by filtration. The residue was purified by flash columnchromatography to give the title compound as a yellow sold (622 mg,42.0% yield).

Step C:(R)-2-(((1-Acryloylpiperidin-3-yl)amino)methyl)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

To a solution of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbaldehyde(100 mg, 0.25 mmol) and 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one(Intermediate 15, 71 mg, 0.37 mmol) in DCM/MeOH (20 mL) was addedNaBH(AcO)₃ (158 mg, 0.745 mmol) and was stirred at rt for 18 h. To thereaction mixture was added NaBH₄ (19 mg, 0.50 mmol) and was stirred for10 min, then water was added and the mixture was extracted with DCM,concentrated to dryness, and purified by flash column chromatography togive the title compound as a slight yellow solid (45 mg, 32% yield). MS(ESI): mass calcd. for C₃₀H₂₉N₅O₃S, 539.6; m/z found, 540.0 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.20-8.03 (m, 1H), 7.48-7.32 (m, 2H), 7.29-7.20(m, 1H), 7.19-7.11 (m, 1H), 7.11-7.02 (m, 3H), 6.99-6.90 (m, 1H),6.82-6.65 (m, 1H), 6.29-6.06 (m, 1H), 5.97-5.87 (m, 1H), 5.77-5.63 (m,1H), 4.25-4.10 (m, 1H), 4.11-3.73 (m, 3H), 3.41-3.33 (m, 0.5H),3.19-2.92 (m, 1.5H), 2.80-2.61 (m, 1H), 2.12 (s, 3H), 2.07-1.95 (m, 1H),1.88-1.70 (m, 1H), 1.62-1.40 (m, 2H).

Example 391:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butylmethyl(2-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidin-1-yl)-2-oxoethyl)carbamate

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 159, 150 mg, 0.29 mmol), N-Boc-N-methylglycine (109 mg, 0.574mmol), HATU (142 mg, 0.373 mmol), and DIEA (111 mg, 0.861 mmol) in DMF(5 mL) was stirred at rt for 1 h. The reaction mixture was purified byflash column chromatography to give the title compound as a light yellowsolid (159 mg, 84.3% yield).

Step B:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added (R)-tert-butylmethyl(2-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidin-1-yl)-2-oxoethyl)carbamate(159 mg, 0.242 mmol), concentrated HCl (5 mL), and MEOH (5 mL) and wasstirred at rt for 1 h. The mixture was concentrated to dryness and waspurified by flash column chromatography to give the title compound as awhite solid (118 mg, 81.0% yield). MS (ESI): mass calcd. forC₂₉H₂₈N₆O₄S, 556.6; m/z found, 557.3 [M+H]⁺. 1H NMR (400 MHz, CD₃OD): δ8.34-8.30 (m, 1H), 7.42-7.36 (m, 2H), 7.32-7.27 (m, 1H), 7.20-7.14 (m,1H), 7.10-7.03 (m, 3H), 7.00-6.94 (m, 1H), 6.10-6.03 (m, 1H), 4.68-4.56(m, 1H), 3.98-3.91 (m, 2H), 3.89-3.80 (m, 1H), 3.74-3.63 (m, 1H),3.60-3.42 (m, 2H), 2.76-2.70 (m, 3H), 2.42-2.13 (m, 2H), 2.11 (s, 3H)

Example 392:(R)—N-(1-(2-Aminoacetyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl(2-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidin-1-yl)-2-oxoethyl)carbamate

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 159, 150 mg, 0.29 mmol), N-Boc-glycine (100 mg, 0.57 mmol),HATU (142 mg, 0.373 mmol), and DIEA (111 mg, 0.861 mmol) in DMF (5 mL)was stirred at rt for 1 h. The mixture was purified by flash columnchromatography to give the title compound as a light yellow solid (151mg, 81.9% yield).

Step B:(R)—N-(1-(2-Aminoacetyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added (R)-tert-butyl(2-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidin-1-yl)-2-oxoethyl)carbamate(151 mg, 0.235 mmol), concentrated HCl (5 mL), and MeOH (5 mL) and wasstirred at rt for 1 h. The reaction mixture was concentrated to drynessand the residue was purified by flash column chromatography to give thetitle compound as a white solid (116 mg, 83.8% yield). MS (ESI): masscalcd. for C₂₈H₂₆N₆O₄S, 542.6; m/z found, 543.3 [M+H]⁺. 1H NMR (400 MHz,CD3OD): δ 8.34-8.30 (m, 1H), 7.42-7.36 (m, 2H), 7.32-7.27 (m, 1H),7.20-7.14 (m, 1H), 7.10-7.03 (m, 3H), 7.00-6.94 (m, 1H), 6.10-6.03 (m,1H), 4.68-4.56 (m, 1H), 3.90-3.78 (m, 3H), 3.74-3.63 (m, 1H), 3.60-3.42(m, 2H), 2.42-2.13 (m, 2H), 2.11 (s, 3H)

Example 393:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(2-(piperidin-1-yl)acetyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)—N-(1-(2-chloroacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 396, 150 mg, 0.26 mmol) in DCM (2 mL) and triethylamine (52 mg,0.52 mmol) was added piperidine (44 mg, 0.52 mmol) in DCM (2 mL)dropwise and it was stirred at rt for 2 h. The reaction mixture wasconcentrated to dryness and was purified by flash column chromatographyand preparative TLC to give the title compound as a yellow solid (37mg). MS (ESI): mass calcd. for C₃₄H₃₆N₆O₄S, 624.8; m/z found, 625.2[M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 8.36 (br, 1H), 8.24 (d, J=5.3 Hz,1H), 7.48-7.40 (m, 2H), 7.36-7.26 (m, 1H), 7.22-7.16 (m, 1H), 7.14-7.09(m, 2H), 7.10-7.05 (m, 1H), 7.00-6.93 (m, 1H), 5.86 (d, J=5.3 Hz, 1H),4.31-3.70 (m, 3H), 3.19-2.98 (m, 3H), 2.88-2.71 (m, 1H), 2.49-2.32 (m,4H), 2.05 (s, 3H), 1.95-1.89 (m, 1H), 1.80-1.60 (m, 2H), 1.55-1.49 (m,4H), 1.45-1.28 (m, 3H).

Example 394:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-morpholinoacetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)—N-(1-(2-chloroacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 396, 150 mg, 0.26 mmol) and triethylamine (43 mg, 0.43 mmol) inDCM (2 mL) was added morpholine (38 mg, 0.43 mmol) in DCM (2 mL)dropwise and was stirred at rt for 2 h. The reaction mixture wasconcentrated to dryness and was purified by flash column chromatography,then preparative TLC to give the title compound as a yellow solid (80mg). MS (ESI): mass calcd. for C₃₃H₃₄N6O5S, 626.7; m/z found, 627.2[M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 10.22 (br, 1H), 8.34-8.14 (m, 2H),7.48-7.36 (m, 2H), 7.36-7.25 (m, 1H), 7.21-7.14 (m, 1H), 7.13-7.07 (m,2H), 7.08-7.03 (m, 1H), 6.98-6.91 (m, 1H), 5.95-5.79 (m, 1H), 4.31-3.70(m, 3H), 3.63-3.48 (m, 4H), 3.21-2.92 (m, 3H), 2.71-2.57 (m, 1H),2.45-2.24 (m, 4H), 2.03 (s, 3H), 1.94-1.86 (m, 1H), 1.78-1.31 (m, 3H).

Example 395:(R)—N-(1-(2-Chloroacetyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G and using2-chloroacetyl chloride in place of prop-2-enoyl chloride in step I toyield the title compound. MS (ESI): mass calcd. for C₂₈H₂₄ClN₅O₄S,562.0; m/z found, 562.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.31-10.14(m, 1H), 8.43-8.25 (m, 2H), 7.47-7.39 (m, 2H), 7.39-7.34 (m, 1H),7.22-7.15 (m, 1H), 7.14-7.06 (m, 3H), 7.00-6.94 (m, 1H), 6.04-5.92 (m,1H), 4.57-4.39 (m, 1H), 4.35-4.23 (m, 2H), 3.84-3.36 (m, 4H), 2.22-2.10(m, 1H), 2.05 (s, 3H), 2.04-1.89 (m, 1H).

Example 396:(R)—N-(1-(2-Chloroacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G and using2-chloroacetyl chloride in place of prop-2-enoyl chloride in step I toyield the title compound. MS (ESI): mass calcd. for C₂₉H₂₆ClN₅O₄S,576.1; m/z found, 576.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.29-10.12(m, 1H), 8.33 (d, J=5.5 Hz, 1H), 8.17-7.96 (m, 1H), 7.49-7.39 (m, 2H),7.39-7.34 (m, 1H), 7.22-7.15 (m, 1H), 7.14-7.05 (m, 3H), 7.00-6.94 (m,1H), 5.98 (d, J=5.5 Hz, 1H), 4.42-4.10 (m, 3H), 3.94-3.70 (m, 2H),3.13-2.94 (m, 1H), 2.78-2.58 (m, 1H), 2.05 (s, 3H), 1.96-1.90 (m, 1H),1.79-1.71 (m, 1H), 1.65-1.38 (m, 2H).

Example 397:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(thiophen-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(4-oxo-5-(4-(thiophen-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a 2-5 mL Biotage microwave vial with stir bar were added1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride*DCM complex(2.3 mg, 0.0028 mmol), 2-chloro-4-iodonicotinonitrile (39.9 mg, 0.151mmol), 4-thiophen-2-ylphenylamine (26.8 mg, 0.153 mmol), and Cs₂CO₃ (71mg, 0.22 mmol) under air at room temperature. The vial was sealed, and1,4-dioxane (0.3 mL) was added via syringe, and quicklyevacuated/flushed with argon 4×. The mixture was stirred at 150° C.under argon for 30 min. The reaction was treated with (R)-tert-butyl3-(2-mercaptoacetamido)piperidine-1-carboxylate (Intermediate 22) (0.24mL, 0.156 mmol) via syringe at room temperature, and stirred under argonat 150° C. for 15 min. The amber mixture was then cooled to roomtemperature, opened, and treated with CDI (102 mg, 0.629 mmol) in oneportion under air. The microwave vial was resealed, evacuated/flushedwith argon 4×, and stirred at 150° C. under argon for 15 min. Thereaction was then cooled to room temperature, diluted with EtOAc (10mL), and washed with 0.5 M citric acid/brine (2×5 mL; final pH˜1-2) and2 M K₂CO₃ (1×5 mL; final pH>10). The clear amber organic phase was thendried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. Theresidue was dissolved in DCM (0.75 mL) and purified by flash columnchromatography to give the title compound as a yellow foam (48 mg, 55%).

Step B:(R)-4-Oxo-N-(piperidin-3-yl)-5-(4-(thiophen-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(4-oxo-5-(4-(thiophen-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(48 mg, 0.083 mmol) in 1,4-dioxane (0.417 mL) was treated with HCl (4.08M in dioxane, 1.02 mL) in one portion at room temperature, and theresulting homogeneous solution was stirred at room temperature for 3 h.After 3 h, the opaque slurry was concentrated to dryness, and theresidue was suspended in CH₃CN (3 mL) and the CH₃CN was removed bysuction and the precipitate was dried under high vacuum to give thetitle compound as a light yellow powder (42.3 mg, 99%).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(thiophen-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-4-oxo-N-(piperidin-3-yl)-5-(4-(thiophen-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(34.5 mg, 0.0674 mmol) in triethylamine (0.066 mL, 0.48 mmol) and DCM(6.1 mL) under argon (evacuated/flushed 2×) was stirred at −40 to −45°C. (dry ice/CH₃CN bath temperature) while acryloyl chloride (0.64 mL,0.064 mmol) was added dropwise over 3.5 min. After 20 min the coldreaction was quenched with an equal volume of 0.1 M NaH₂PO₄ (pH˜5, 7 mL,0.7 mmol; final pH˜6-7). The organic layer was dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness and dried under highvacuum to provide a crude residue as a dark yellow solid. This residuewas purified by HPLC to give the title compound as a light beige foam(12.2 mg, 34.0% yield). MS (ESI): mass calcd. for C₂₇H₂₃N₅O₃S₂, 529.6;m/z found, 530.25 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ ppm (ROTAMERS) 9.49(br. s., 1H), 8.31-8.41 (m, 1H), 7.81 (d, J=8.6 Hz, 2H), 7.31-7.42 (m,4H), 7.13 (dd, J=5.1 Hz, J=3.8 Hz, 1H), 6.58-6.69 (m, 1H), 6.15-6.48 (m,2.5H), 5.71-5.82 (m, 1H), 5.49-5.56 (m, 0.5H), 3.88-4.23 (m, 2.5H),3.29-3.74 (m, 2.5H), 1.67-2.14 (m, 4H).

Example 398:(R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

A solution of 5-(*R)(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 63, 100 mg, 0.24 mmol), HATU (183 mg, 0.481 mmol),and triethylamine (73 mg, 0.72 mmol) in anhydrous DMF (3 mL) was stirredat room temperature for 10 min, then tert-butyl(3R)-3-aminopiperidine-1-carboxylate (72 mg, 0.36 mmol) was added andthe mixture was stirred for 2 h. The crude mixture was purified by flashcolumn chromatography to give the title compound as a slight yellowsolid (110 mg, 76% yield).

Step B:(R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(110 mg, 0.18 mmol) in HCl/MeOH (6 N, 15 mL) was concentrated at 50° C.to dryness to give a yellow solid. A solution of(E)-2-cyano-4,4-dimethyl-pent-2-enoic acid (Intermediate 44, 34 mg, 0.22mmol), HATU (139 mg, 0.366 mmol), and triethylamine (56 mg, 0.55 mmol)in anhydrous DMF (3 mL) was stirred at room temperature for 10 min, thenthe yellow solid from above was added and the mixture was stirred for 2h. The reaction mixture was purified by flash column chromatography togive the title compound as a slight yellow solid (75 mg, 64% yield). MS(ESI): mass calcd. for C₃₅H₃₄N₆O₄S, 634.7; m/z found, 635.3 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.32 (d, J=5.5 Hz, 1H), 7.45-7.35 (m, 2H),7.32-7.25 (m, 1H), 7.22-7.13 (m, 1H), 7.12-7.03 (m, 3H), 6.98-6.93 (m,1H), 6.86 (s, 1H), 6.07 (d, J=5.5 Hz, 1H), 4.57-3.88 (m, 3H), 3.29-2.78(m, 2H), 2.12 (s, 3H), 2.10-2.02 (m, 1H), 1.99-1.56 (m, 3H), 1.28 (s,9H).

Example 399:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (E)-2-Cyano-3-cyclopropylacryloyl chloride

To a suspension of (E)-2-cyano-3-cyclopropyl-prop-2-enoic acid(Intermediate 17) (24 mg, 0.18 mmol) in CHCl₃ (0.5 mL) was added1-chloro-N,N,2-trimethylpropenylamine (28 μL, 0.22 mmol) and was mixedfor 5 minutes before being used directly in the next reaction.

Step B:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of triethylamine (68 μL, 0.49 mmol) and(R)-5-(4-isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamidehydrochloride (79.3 mg, 0.162 mmol) in DCM (1 mL) was cooled in an icewater bath. To the reaction mixture was added a solution of(E)-2-cyano-3-cyclopropylacryloyl chloride (0.179 mmol) in CHCl₃ (0.5mL) and the reaction mixture was stirred at 0° C. for 40 min. Thereaction mixture was partitioned between DCM (10 mL) and saturatedaqueous NaHCO₃ (10 mL). The aqueous phase was extracted once with EtOAc(10 mL) and the combined organic extracts were dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby flash column chromatography to give the title compound as a lightyellow powder (38.0 mg, 41% yield). MS (ESI): mass calcd. forC₃₀H₃₀N₆O₄S, 570.7; m/z found, 571.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 10.12 (s, 1H), 8.33 (d, J=5.56 Hz, 1H), 8.11 (d, J=7.07 Hz, 1H), 7.34(d, J=8.08 Hz, 2H), 7.10 (d, J=9.09 Hz, 2H), 6.62 (d, J=11.12 Hz, 1H),6.04 (d, J=5.56 Hz, 1H), 4.70 (spt, J=6.06 Hz, 1H), 3.80-4.31 (m, 3H),2.67-3.27 (m, 2H), 1.76-1.98 (m, 3H), 1.61-1.76 (m, 1H), 1.41-1.60 (m,1H), 1.33 (d, J=6.06 Hz, 6H), 0.78-1.29 (m, 4H).

Example 400:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide*HCl(Example 405 step E, 93.2 mg, 0.191 mmol) in DCM (1 mL) was addedtriethylamine (79 μL, 0.57 mmol) followed by acryloyl chloride (15 μL,0.19 mmol) dropwise via syringe. The resulting suspension was stirredunder air at 0° C. for 40 min. The reaction mixture was partitionedbetween DCM (10 mL) and saturated aqueous NaHCO₃ (10 mL). The aqueousphase was extracted once with EtOAc (10 mL) and the combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was purified by flash column chromatography to givethe title compound as a yellow powder (32.2 mg, 33.3% yield). MS (ESI):mass calcd. for C₂₆H₂₇N₅O₄S, 505.6; m/z found, 506.2 [M+H]⁺. ¹H NMR (400MHz, CDCl3): δ 9.46 (s, 1H), 8.34 (br. s., 1H), 7.22 (d, J=7.58 Hz, 2H),7.04 (d, J=8.59 Hz, 2H), 6.63 (dd, J=10.86, 16.93 Hz, 1H), 6.28-6.49 (m,1H), 6.24 (br. s., 0.5H), 6.06-6.19 (m, 1H), 5.68-5.82 (m, 1H), 5.49(br. s., 0.5H), 4.60 (spt, J=5.98 Hz, 1H), 3.84-4.24 (m, 2.5H),3.28-3.77 (m, 2.5H), 1.68-2.14 (m, 4H), 1.39 (d, J=6.06 Hz, 6H).

Example 401:(R,E)-N-(1-(3-Cyclopropyl-2-methylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg, 0.28 mmol),(E)-3-cyclopropyl-2-methyl-prop-2-enoic acid (Intermediate 42, 71 mg,0.56 mmol), HATU (138 mg, 0.364 mmol), and DIEA (108 mg, 0.840 mmol) inDMF (5 mL) was stirred at rt for 1 h. The mixture was purified by flashcolumn chromatography to give the title compound as light yellow solid(58 mg, 34% yield). MS (ESI): mass calcd. for C₃₄H₃₃N₅O₄S, 607.7; m/zfound, 608.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35-8.31 (m, 1H),7.43-7.36 (m, 2H), 7.32-7.27 (m, 1H), 7.19-7.13 (m, 1H), 7.11-7.04 (m,3H), 7.00-6.94 (m, 1H), 7.09-6.05 (m, 1H), 5.06-4.98 (m, 1H), 4.35-3.84(m, 3H), 3.14-2.83 (m, 2H), 2.12 (s, 3H), 2.10-1.98 (m, 1H), 1.98-1.90(m, 3H), 1.90-1.78 (m, 1H), 1.78-1.64 (m, 1H), 1.64-1.49 (m, 2H),0.90-0.78 (m, 2H), 0.56-0.45 (m, 1H), 0.45-0.37 (m, 1H).

Example 402:(R,EZ)—N-(1-(2-Chloro-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 150 mg 0.28 mmol),(EZ)-2-chloro-3-cyclopropyl-prop-2-enoic acid (Intermediate 39, 82 mg,0.56 mmol), HATU (138 mg, 0.364 mmol), and DIEA (108 mg, 0.840 mmol) inDMF (5 mL) was stirred at rt for 1 h. The mixture was purified by flashcolumn chromatography to give the title compound as a light yellow solid(68 mg, 39% yield). MS (ESI): mass calcd. for C₃₃H₃₀ClN₅O₄S, 628.1; m/zfound, 628.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34-8.28 (m, 1H),7.42-7.33 (m, 2H), 7.33-7.26 (m, 1H), 7.19-7.11 (m, 1H), 7.10-7.01 (m,3H), 6.99-6.92 (m, 1H), 6.09-6.02 (m, 1H), 5.60-5.36 (m, 1H), 4.35-3.84(m, 3H), 3.19-2.83 (m, 2H), 2.15-1.98 (m, 4H), 1.95-1.78 (m, 2H),1.77-1.67 (m, 1H), 1.67-1.51 (m, 1H), 0.96-0.78 (m, 2H), 0.70-0.60 (m,1H), 0.60-0.47 (m, 1H).

Example 403:(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-morpholinobut-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869, 200 mg, 0.40 mmol) and (E)-4-morpholinobut-2-enoic acid(171 mg, 1.00 mmol) in anhydrous DMF (3 mL) were added HATU (228 mg,0.600 mmol) and diisopropylethylamine (78 mg, 0.60 mmol) and the mixturewas stirred at rt overnight. The reaction mixture was purified by flashcolumn chromatography to give the title compound as a yellow solid (74mg). MS (ESI): mass calcd. for C₃₅H₃₆N₆O₅S, 652.8; m/z found, 653.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.33-10.13 (m, 1H), 8.33 (d, J=5.5Hz, 1H), 8.18-8.08 (m, 1H), 7.46-7.40 (m, 2H), 7.40-7.33 (m, 1H),7.21-7.16 (m, 1H), 7.14-7.05 (m, 3H), 7.00-6.93 (m, 1H), 6.67-6.50 (m,2H), 5.97 (d, J=5.5 Hz, 1H), 4.46-3.73 (m, 4H), 3.65-3.35 (m, 6H),3.15-2.58 (m, 3H), 2.43-2.28 (m, 2H), 2.05 (s, 3H), 1.94-1.87 (m, 1H),1.83-1.54 (m, 2H), 1.46-1.36 (m, 1H).

Example 404:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(benzo[b]thiophen-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-(benzo[b]thiophen-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared using step A in Example 397, and using1-benzothiophen-5-amine in place of 4-thiophen-2-ylphenylamine in step Bto yield the title compound.

Step B:(R)-5-(Benzo[b]thiophen-5-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(benzo[b]thiophen-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(54.4 mg, 0.0990 mmol) in dioxane (0.5 mL, 0.1 mmol) was treated withHCl (4.08 M in dioxane, 1.21 mL) in one portion at room temperature, andthe resulting solution was stirred at room temperature for 3 h, then itwas concentrated to dryness. The residue was suspended in CH₃CN (3 mL)and the CH₃CN supernatant was suctioned off by pipette, and the wetsolids were dried under high vacuum to give the title compound as alight yellow powder (47 mg, 98% yield).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(benzo[b]thiophen-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(benzo[b]thiophen-5-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(36.6 mg, 0.0753 mmol) in triethylamine (34.1 mg, 0.337 mmol) and DCM(6.85 mL) under argon (evacuated/flushed 2×) was stirred at −40° C. to−45° C. (dry ice/CH₃CN bath temperature) while acryloyl chloride (0.73mL, 0.072 mmol) was added dropwise over 3.5 min. After 20 min, the coldreaction was quenched with an equal volume of 0.1 M NaH₂PO₄ (pH˜5, 7 mL,0.7 mmol; final pH˜6-7). The organic layer was dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness and dried under highvacuum to provide a crude residue. This residue was purified by HPLC togive the title compound as a light beige foam (10.7 mg, 28.2% yield). MS(ESI): mass calcd. for C₂₅H₂₁N₅O₃S₂, 503.6; m/z found, 504.3 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): δ (ROTAMERS) 9.51 (s, 1H), 8.32 (d, J=5.05 Hz,1H), 8.07 (d, J=8.59 Hz, 1H), 7.82 (br. s., 1H), 7.60 (d, J=5.56 Hz,1H), 7.36-7.43 (m, 1H), 7.27-7.32 (m, 1H), 6.57-6.70 (m, 1H), 6.25-6.49(m, 1.5H), 6.11 (br. s., 1H), 5.69-5.82 (m, 1H), 5.62 (br. s., 0.5H),3.85-4.24 (m, 2.5H), 3.27-3.79 (m, 2.5H), 1.90-2.14 (m, 2H), 1.73-1.87(m, 2H). 3.24-3.18 (m, 2H), 2.05 (s, 3H), 1.78 (s, 3H).

Example 405:(R)-5-(4-Isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-Chloro-4-(4-isopropoxyanilino)pyridine-3-carbonitrile

To a 10-20 mL microwave vial was added sequentially2-chloro-4-iodonicotinonitrile (300 mg, 1.13 mmol), 4-isopropoxyaniline(172 mg, 1.13 mmol), palladium(II) acetate (5.0 mg, 0.023 mmol),bis(2-diphenylphosphinophenyl)ether (18 mg, 0.034 mmol), and Cs₂CO₃ (517mg, 1.59 mmol) and the vial was sealed and evacuated and refilled withargon three times. To this vial was added 1,4-dioxane (2.2 mL) and thevial was evacuated and refilled with argon once. The reaction mixturewas heated for 5 minutes in a 50° C. oil bath under an argon inletneedle, then the inlet needle was removed and the sealed vial was heatedfor 30 minutes in a 150° C. oil bath. The crude reaction mixture wasused directly in the next step (326 mg).

Step B: tert-Butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate

To a 10-20 mL microwave vial was added (R)-1-Boc-3-aminopiperidine(5.015 g, 25.04 mmol). The vial was sealed and evacuated and back-filledwith argon three times and then methyl 2-mercaptoacetate (6.7 mL, 75mmol) was added via syringe in one portion and the vial was heated in a150° C. oil bath. After 1 h 35 minutes, the mixture was cooled to rt andwas purified by flash column chromatography to give the title compound(5.54 g, 80.6% yield).

Step C: (R)-tert-Butyl3-(3-amino-4-((4-isopropoxyphenyl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate

To the sealed tube containing2-chloro-4-(4-isopropoxyanilino)pyridine-3-carbonitrile (326 mg, 1.13mmol) was added a 0.5 M solution of tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate in dioxane (0.5M, 2.7 mL, 1.4 mmol). The resulting brown suspension was heated in thesealed tube in a 150° C. oil bath for 15 minutes. The mixture was cooledto room temperature to give the title compound as a crude mixture (596mg), which was used in the next reaction without purification.

Step D: (R)-tert-Butyl3-(5-(4-isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To the crude mixture of (R)-tert-butyl3-(3-amino-4-((4-isopropoxyphenyl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate(from above reaction) was added CDI (0.736 g, 4.54 mmol). The tube wassealed and the vessel was evacuated and refilled with argon twice. Themixture was heated for 5 minutes in a 50° C. oil bath under an argoninlet needle, then the argon inlet needle was removed and the mixturewas heated at 150° C. for 10 minutes. The mixture was cooled to roomtemperature and the mixture was partitioned between EtOAc (50 mL) andwater (50 mL). The aqueous phase was extracted with EtOAc (2×50 mL) andthe combined organic extracts were washed with saturated aqueous NaCl(50 mL), followed by 1 N aqueous HCl (50 mL). The organic phase wasdried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. Theresidue was purified by flash column chromatography to give the titlecompound as a tan foamy solid (449 mg 71.8% yield).

Step E:(R)-5-(4-Isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamidehydrochloride

To a solution of (R)-tert-butyl3-(5-(4-isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(421.8 mg, 0.765 mmol) in dioxane (4 mL) was added 4 M HCl in dioxane(4.0 mL, 4.0 M, 16 mmol) and was stirred at room temperature under airfor 20 minutes. The reaction mixture was concentrated to dryness and theresidue was dried under vacuum to give the title compound as a tanpowder (459.2 mg, 123.1% yield).

Step F:(R)-5-(4-Isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A portion of(R)-5-(4-isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamidehydrochloride (52 mg, 0.11 mmol) was purified by HPLC to give the titlecompound as a light yellow powder (42.0 mg, 70% yield). MS (ESI): masscalcd. for C₂₃H₂₅N₅O₃S, 451.5; m/z found, 452.1 [M+H]⁺. 1H NMR (400 MHz,DMSO-d6) δ 10.17 (s, 1H), 8.62-8.80 (m, 2H), 8.38 (d, J=5.56 Hz, 1H),8.21 (d, J=7.07 Hz, 1H), 7.38 (d, J=7.58 Hz, 2H), 7.15 (d, J=9.09 Hz,2H), 6.09 (d, J=5.56 Hz, 1H), 4.74 (spt, J=5.89 Hz, 1H), 4.14-4.26 (m,1H), 3.24-3.43 (m, 2H), 2.80-2.95 (m, 2H), 1.88-2.02 (m, 2H), 1.60-1.82(m, 2H), 1.37 (d, 6H).

Example 406:(R)-5-(4-Isopropoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 405, 88.8 mg, 0.182 mmol) in DCM (1 mL) was added triethylamine(76 μL, 0.55 mmol). The resulting solution was cooled in an ice bath andpropionyl chloride (16 μL, 0.18 mmol) was added dropwise via amicroliter syringe and the resulting orange solution was stirred underair in the ice bath for 25 min. The reaction mixture was partitionedbetween DCM (10 mL) and saturated aqueous NaHCO₃ (10 mL). The aqueousphase was extracted once with EtOAc (10 mL) and the combined organicextracts were dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was purified by flash column chromatography to givethe title compound as a light yellow powder (41.5 mg, 44.9% yield). MS(ESI): mass calcd. for C₂₆H₂₉N₅O₄S, 507.6; m/z found, 508.3 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆, 1:1 mixture of rotamers): δ 10.18 (s, 0.5H),10.12 (s, 0.5H), 8.33 (d, J=5.56 Hz, 1H), 8.10 (d, J=7.07 Hz, 0.5H),8.02 (d, J=7.58 Hz, 0.5H), 7.34 (d, J=9.09 Hz, 2H), 7.10 (d, J=9.09 Hz,2H), 6.01-6.05 (m, 1H), 4.70 (spt, J=5.98 Hz, 1H), 4.33-4.50 (m, 0.5H),4.19-4.27 (m, 0.5H), 3.70-3.95 (m, 2H), 2.86-3.02 (m, 1H), 2.53-2.68 (m,1H), 2.30-2.38 (m, 2H), 1.87-1.97 (m, 1H), 1.35-1.80 (m, 3H), 1.33 (d,J=6.06 Hz, 6H), 1.01 (q, J=7.07 Hz, 3H).

Example 407:(R)-4-Oxo-N-(piperidin-3-yl)-5-(4-(thiophen-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using step A-B in Example 397, to yieldthe title compound. MS (ESI): mass calcd. for C₂₄H₂₁N₅O₂S₂, 475.6; m/zfound, 476.25 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ ppm 8.46 (d, J=6.6 Hz,1H), 7.91 (d, J=8.6 Hz, 2H), 7.54 (d, J=2.5 Hz, 1H), 7.45-7.51 (m, 3H),7.13-7.19 (m, 1H), 6.43 (d, J=6.6 Hz, 1H), 4.22-4.35 (m, 1H), 3.55 (dd,J=12.4, 4.3 Hz, 1H), 3.37 (d, J=12.6 Hz, 1H), 2.91-3.03 (m, 2H),2.04-2.17 (m, 2H), 1.70-1.93 (m, 2H).

Example 408:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenoxybenzyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using (4-phenoxyphenyl)methanamine (Intermediate35) in place of 2-methyl-4-phenoxy-aniline in step C and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G to yield thetitle compound. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₄S, 553.6; m/z found,554.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.12 (s, 1H), 8.35 (d, J=5.4Hz, 1H), 8.25-8.02 (m, 1H), 7.47-7.27 (m, 4H), 7.18-7.05 (m, 1H),7.02-6.89 (m, 4H), 6.85-6.65 (m, 2H), 6.17-5.99 (m, 1H), 5.69-5.61 (m,1H), 5.07 (s, 2H), 4.53-4.12 (m, 1H), 4.07-3.88 (m, 1H), 3.84-3.69 (m,1H), 3.1-2.90 (m, 1H), 2.85-2.58 (m, 1H), 1.98-1.85 (m, 1H), 1.81-1.72(m, 1H), 1.69-1.54 (m, 1H), 1.50-1.33 (m, 1H).

Example 409:(R)—N-(1-Methylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxybenzyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-4-Oxo-5-(4-phenoxybenzyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using (4-phenoxyphenyl)methanamine (Intermediate35) in place of 2-methyl-4-phenoxy-aniline in step C and usingtert-butyl (3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G to yield thetitle compound.

Step B:(R)—N-(1-Methylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxybenzyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-4-oxo-5-(4-phenoxybenzyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.21 mmol) in DCM (5 mL) were added formaldehyde (0.5 mL, 37wt. % in H₂O) and NaBH(OAc)₃ (90 mg, 0.43 mmol) and was stirred at roomtemperature for 1 h. The reaction mixture was concentrated to drynessand the residue was purified by flash column chromatography to give thetitle compound as a yellow solid (40 mg, 36% yield). MS (ESI): masscalcd. for C₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.2 [M+H]+. 1H NMR (400 MHz,CD3OD): δ 8.30 (d, J=5.6 Hz, 1H), 7.35-7.22 (m, 4H), 7.09-7.02 (m, 1H),6.90-6.84 (m, 4H), 6.72 (d, J=5.6 Hz, 1H), 5.08 (s, 2H), 4.65-4.55 (m,1H), 3.63-3.37 (m, 3H), 3.26-3.16 (m, 1H), 2.90 (s, 3H), 2.58-2.32 (m,1H), 2.29-2.16 (m, 1H).

Example 410:(R)-5-(Benzo[b]thiophen-5-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using steps A-B in Example 404, to yieldthe title compound. MS (ESI): mass calcd. for C₂₂H₁₉N₅O₂S₂, 449.6; m/zfound, 450.25 [M+H]⁺. ¹H NMR (400 MHz, CD3OD): δ ppm 8.40 (d, J=6.6 Hz,1H), 8.18 (d, J=8.6 Hz, 1H), 7.97 (s, 1H), 7.78 (d, J=5.6 Hz, 1H), 7.49(d, J=5.6 Hz, 1H), 7.39 (d, J=8.6 Hz, 1H), 6.29 (d, J=6.1 Hz, 1H),4.24-4.35 (m, 1H), 3.51-3.60 (m, 1H), 3.37 (d, J=12.6 Hz, 1H), 2.91-3.04(m, 2H), 2.04-2.16 (m, 2H), 1.71-1.93 (m, 2H).

Example 411:(R)—N-(1-Methylpiperidin-3-yl)-4-oxo-5-(4-phenoxybenzyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-4-Oxo-5-(4-phenoxybenzyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using (4-phenoxyphenyl)methanamine (Intermediate35) in place of 2-methyl-4-phenoxy-aniline in step C and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G to yield thetitle compound.

Step B:(R)—N-(1-Methylpiperidin-3-yl)-4-oxo-5-(4-phenoxybenzyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-4-oxo-5-(4-phenoxybenzyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(73 mg, 0.15 mmol) in DCM (5 mL) were added formaldehyde (0.5 mL, 37 wt.% in H₂O) and NaBH(OAc)₃ (61 mg, 0.29 mmol) and was stirred at roomtemperature for 1 h. The reaction mixture was concentrated to drynessand the residue was purified by flash column chromatography to give thetitle compound as a yellow solid (54 mg, 66% yield). MS (ESI): masscalcd. for C₂₈H₂₇N₅O₃S, 513.6; m/z found, 514.2 [M+H]⁺. 1H NMR (400 MHz,CD3OD): δ 8.41 (s, 1H), 8.33 (d, J=5.5 Hz, 1H), 7.40-7.24 (m, 4H),7.11-7.02 (m, 1H), 6.95-6.85 (m, 4H), 6.75 (d, J=5.6 Hz, 1H), 5.11 (s,2H), 4.37-4.18 (m, 1H), 3.55-3.42 (m, 1H), 3.29-3.23 (m, 1H), 2.90-2.83(m, 2H), 2.80 (s, 3H), 2.10-1.97 (m, 2H), 1.92-1.78 (m, 1H), 1.72-1.60(m, 1H).

Example 412:(R)-4-Oxo-5-(4-phenoxybenzyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using steps A in Example 411, to yieldthe title compound. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S, 499.6; m/zfound, 500.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30 (d, J=5.5 Hz, 1H),7.40-7.25 (m, 4H), 7.12-7.02 (m, 1H), 6.97-6.88 (m, 4H), 6.71 (d, J=5.7Hz, 1H), 5.13 (s, 2H), 4.18-4.02 (m, 1H), 3.26-3.18 (m, 1H), 3.07-2.97(m, 1H), 2.84-2.64 (m, 2H), 2.08-1.96 (m, 1H), 1.92-1.83 (m, 1H),1.74-1.61 (m, 2H).

Example 413:(R)-5-(2-Methyl-4-(trifluoromethoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-Chloro-6-[2-methyl-4-(trifluoromethoxy)anilino]benzonitrile

To a 10-20 mL microwave vial were added sequentially2-chloro-4-iodonicotinonitrile (300 mg, 1.14 mmol),2-methyl-4-(trifluoromethoxy)aniline (217 mg, 1.14 mmol), palladium(II)acetate (5.0 mg, 0.023 mmol), bis(2-diphenylphosphinophenyl)ether (18mg, 0.034 mmol), and Cs₂CO₃ (518 mg, 1.60 mmol). The vial was sealed andwas evacuated and refilled with argon three times and dioxane (2.2 mL)was added. The vial was evacuated and refilled with argon once. Thesuspension was heated for 5 minutes in a 50° C. oil bath under the argoninlet needle, then the inlet needle was removed and the sealed vial washeated for 30 minutes in a 150° C. oil bath. The crude product was useddirectly in the next reaction (372 mg).

Step B: (R)-tert-Butyl3-(3-amino-4-((2-methyl-4-(trifluoromethoxy)phenyl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate

To a sealed tube containing2-chloro-6-[2-methyl-4-(trifluoromethoxy)anilino]benzonitrile (372 mg,1.14 mmol) was added a 0.5 M solution of tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate22) (2.72 mL, 1.36 mmol) in dioxane. The reaction mixture was heated inthe sealed tube in a 150° C. oil bath for 15 minutes. The mixture wascooled to room temperature and used directly in the next reaction (642mg).

Step C: (R)-tert-butyl3-(5-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To the crude reaction mixture containing (R)-tert-butyl3-(3-amino-4-((2-methyl-4-(trifluoromethoxy)phenyl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate(642 mg, 1.14 mmol) was added CDI (0.745 g, 4.60 mmol). The tube wassealed and the vessel was evacuated and refilled with argon twice. Themixture was heated for 5 minutes in a 50° C. oil bath under an argoninlet needle, then the argon inlet needle was removed and the mixturewas heated at 150° C. for 10 minutes. The mixture was cooled to roomtemperature, water was added, and the aqueous phase was extracted withEtOAc (2×50 mL) and the combined organic extracts were washed with 1 Maqueous HCl (50 mL) followed by saturated aqueous NaCl (50 mL). Theorganic phase was dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by flash columnchromatography to give the title compound as a tan solid (452.4 mg,67.37% yield).

Step D:(R)-5-(2-Methyl-4-(trifluoromethoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (R)-tert-butyl3-(5-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(437 mg, 0.738 mmol) in dioxane (4 mL) was added 4 M HCl in dioxane (4mL, 16 mmol) and was stirred at room temperature under air for 1.5 h.The reaction mixture was concentrated to dryness and the residue waspurified by HPLC to give the title compound as a light yellow solid(53.4 mg, 11.9% yield). MS (ESI): mass calcd. for C₂₂H₂₀F₃N₅O₃S, 491.5;m/z found, 492.1 [M+H]⁺. 1H NMR (400 MHz, MeOH) Shift 8.36 (d, J=5.56Hz, 1H), 7.45-7.49 (m, 1H), 7.42-7.45 (m, 1H), 7.35 (d, J=8.59 Hz, 1H),6.06 (d, J=5.56 Hz, 1H), 4.27 (tt, J=3.85, 10.80 Hz, 1H), 3.54 (dd,J=4.04, 12.63 Hz, 1H), 3.32-3.41 (m, 1H), 2.88-3.02 (m, 2H), 2.22 (s,3H), 2.03-2.15 (m, 2H), 1.67-1.94 (m, 2H), 1.24-1.45 (m, 1H).

Example 414:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 413, 150 mg, 0.30 mmol) in DCM (2 mL) was added triethylamine(125 μL, 0.900 mmol) and was cooled in an ice-water bath and to it wasadded acryloyl chloride (24 μL, 0.30 mmol) dropwise via syringe. Thereaction mixture was stirred under air at 0° C. for 1 h. The reactionmixture was partitioned between DCM (10 mL) and saturated aqueous NaHCO₃(10 mL). The aqueous phase was extracted once with EtOAc (10 mL) and thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated to dryness. The residue was purified by flash columnchromatography to give the title compound as a light yellow solid (67.2mg, 41.1% yield). MS (ESI): mass calcd. for C₂₅H₂₂F₃N₅O₄S, 545.5; m/zfound, 546.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d, J=5.56 Hz, 1H),7.49 (d, J=8.59 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J=8.59 Hz, 1H),6.74-6.86 (m, 1H), 6.21 (dd, J=3.03, 16.67 Hz, 1H), 6.03 (d, J=5.56 Hz,1H), 5.70-5.78 (m, 1H), 4.50-4.59 (m, 0.5H), 4.31 (d, J=12.63 Hz, 0.5H),4.18 (d, J=14.65 Hz, 0.5H), 3.90-4.05 (m, 1.5H), 3.11-3.25 (m, 1H),2.83-2.99 (m, 1H), 2.22 (s, 3H), 2.03-2.13 (m, 1H), 1.88 (dt, J=3.60,13.52 Hz, 1H), 1.50-1.84 (m, 2H).

Example 415:(R)-4-Oxo-N-(piperidin-3-yl)-5-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 413 in steps A-D, using 4-(trifluoromethoxy)aniline in place of2-methyl-4-(trifluoromethoxy)aniline in step A to yield the titlecompound. MS (ESI): mass calcd. for C₂₁H₁₈F₃N₅O₃S, 477.5; m/z found,478.0 [M+H]⁺. 1H NMR (400 MHz, MeOH) δ 8.35 (d, J=5.56 Hz, 1H),7.51-7.62 (m, 4H), 6.18 (d, J=5.56 Hz, 1H), 4.27 (tt, J=4.04, 10.86 Hz,1H), 3.53 (dd, J=4.04, 12.13 Hz, 1H), 3.36 (d, J=12.63 Hz, 1H),2.89-3.02 (m, 2H), 2.02-2.15 (m, 2H), 1.69-1.93 (m, 2H), 1.25-1.45 (m,1H).

Example 416:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-4-oxo-N-(piperidin-3-yl)-5-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 415, 77 mg, 0.15 mmol) in DCM (1 mL) and triethylamine (62 μL,0.45 mmol) was cooled in an ice-water bath and to it was added acryloylchloride (12 μL, 0.15 mmol) dropwise via syringe. The reaction mixturewas stirred under air at 0° C. for 1 h. The reaction mixture waspartitioned between DCM (10 mL) and saturated aqueous NaHCO₃ (10 mL).The aqueous phase was extracted once with EtOAc (10 mL) and the combinedorganic extracts were dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by flash columnchromatography to give the title compound as a light yellow solid (25.4mg, 31.9% yield). MS (ESI): mass calcd. for C₂₄H₂₀F₃N₅O₄S, 531.5; m/zfound, 532.2 [M+H]+. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d, J=5.56 Hz, 1H),7.56-7.62 (m, 2H), 7.50-7.56 (m, 2H), 6.73-6.86 (m, 1H), 6.21 (dd,J=3.54, 16.67 Hz, 1H), 6.15 (d, J=5.56 Hz, 1H), 5.74 (t, J=8.84 Hz, 1H),4.51-4.60 (m, 0.5H), 4.31 (d, J=12.13 Hz, 0.5H), 4.14-4.22 (m, 0.5H),3.91-4.05 (m, 1.5H), 3.10-3.23 (m, 1H), 2.82-2.99 (m, 1H), 2.02-2.13 (m,1H), 1.88 (dt, J=3.66, 13.39 Hz, 1H), 1.50-1.83 (m, 2H).

Example 417:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described insteps A-D in Example 33 (including Chiral Resolution Method A after stepF in Example 1 to obtain the *S atropisomer), to yield the titlecompound. MS (ESI): mass calcd. for C₂₇H₂₉N₅O₄S, 519.6; m/z found, 520.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.31 (d, J=5.56 Hz, 1H), 7.21 (d,J=8.59 Hz, 1H), 6.98 (d, J=2.53 Hz, 1H), 6.93 (dd, J=2.53, 8.59 Hz, 1H),6.74-6.86 (m, 1H), 6.21 (dd, J=3.03, 16.67 Hz, 1H), 6.04 (d, J=5.56 Hz,1H), 5.74 (t, J=8.34 Hz, 1H), 4.67 (spt, J=6.06 Hz, 1H), 4.55 (dd,J=2.78, 13.39 Hz, 0.5H), 4.31 (d, J=13.14 Hz, 0.5H), 4.13-4.16 (m,0.5H), 3.90-4.07 (m, 1.5H), 3.10-3.24 (m, 1H), 2.83-3.00 (m, 1H), 2.12(s, 3H), 2.02-2.11 (m, 1H), 1.88 (dt, J=3.66, 13.39 Hz, 1H), 1.48-1.82(m, 2H), 1.35 (d, J=6.06 Hz, 6H).

Example 418:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described insteps A-D in Example 33 (including Chiral Resolution Method A after stepF in Example 1 to obtain the *R atropisomer of the intermediate), toyield the title compound. Absolute stereochemical configuration of thetitle compound was confirmed via X-ray analysis after co-crystallizationwith BTK protein. MS (ESI): mass calcd. for C₂₇H₂₉N₅O₄S, 519.6; m/zfound, 520.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.31 (d, J=5.56 Hz, 1H),7.21 (d, J=8.59 Hz, 1H), 6.98 (d, J=3.03 Hz, 1H), 6.92 (dd, J=2.53, 8.59Hz, 1H), 6.80 (ddd, J=6.57, 10.48, 16.80 Hz, 1H), 6.21 (d, J=16.67 Hz,1H), 6.03 (d, J=5.56 Hz, 1H), 5.74 (dd, J=4.55, 10.61 Hz, 1H), 4.67(spt, J=6.06 Hz, 1H), 4.49-4.59 (m, 0.5H), 4.25-4.37 (m, 0.5H),4.14-4.23 (m, 0.5H), 3.89-4.05 (m, 1.5H), 3.11-3.23 (m, 1H), 2.83-2.98(m, 1H), 2.12 (s, 3H), 2.02-2.10 (m, 1H), 1.88 (dt, J=3.66, 13.39 Hz,1H), 1.49-1.82 (m, 2H), 1.35 (d, J=6.06 Hz, 6H).

Example 419:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(naphthalen-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-(naphthalen-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a 10 mL Biotage microwave vial with a stir bar were added2-aminonaphthalene (217.3 mg, 1.518 mmol),2-chloro-4-iodonicotinonitrile (398.9 mg, 1.508 mmol), Pd(OAc)₂ (7.2 mg,0.032 mmol), DPEPhos (25.4 mg, 0.0472 mmol), and Cs₂CO₃ (696 mg, 2.14mmol). The vial was sealed, treated with dioxane (3 mL),evacuated/flushed with argon 4×, and stirred at 150° C. under argon for30 min. The reaction was then cooled to room temperature, treated withtert-butyl (3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate(Intermediate 22) (2.35 mL, 0.65 M, 1.53 mmol) via syringe,evacuated/flushed with argon 4×, and stirred at 150° C. for 15 min. Thereaction was cooled to room temperature, treated with solid CDI (974.4mg, 6.009 mmol) in one portion under air, resealed and evacuated/flushedwith argon 4×, and stirred at 150° C. for 15 min. The reaction was thendiluted with EtOAc (10 mL), and washed with 0.5 M citric acid/brine (2×8mL) and 2 M K₂CO₃ (1×5 mL). The clear amber organic phase was dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue waspurified by normal phase flash column chromatography (SiO2) to give thetitle compound as an orange-yellow foam (539 mg, 65.7% yield).

Step C:(R)-5-(Naphthalen-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(naphthalen-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(534 mg, 0.982 mmol) in dioxane (4.9 mL) was treated with HCl (3.97 M indioxane, 12.4 mL, 49.2 mmol) in one portion at room temperature, and theresulting mixture was stirred at room temperature for 1 h. The reactionwas concentrated to dryness to give the title compound as a yellow-beigepowder (538.2 mg, 100.2% yield).

Step D:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(naphthalen-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(naphthalen-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(99.7 mg, 0.182 mmol) in DCM (1.25 mL) and MeOH (0.3 mL) was treatedwith triethylamine (76 μL, 0.55 mmol) at room temperature under air, andthe resulting homogeneous orange solution was stirred at 0° C. underpositive argon pressure while acryloyl chloride (14.8 μL, 0.182 mmol)was added dropwise over 50 sec. The resulting solution was stirred at 0°C. for 5 min and was then quenched with 1 M NaH₂PO₄ (3 mL) and extractedwith DCM (1×5 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness. The residue was purified by HPLCto give the title compound as an off-white powder (27.5 mg, 24.7%). MS(ESI): mass calcd. for C₂₇H₂₃N₅O₃S, 497.2; m/z found, 498.1 [M+H]+. 1HNMR (400 MHz, MeOH-d4) δ 8.30 (d, J=5.56 Hz, 1H), 8.11 (d, J=9.09 Hz,1H), 7.94-8.04 (m, 3H), 7.56-7.66 (m, 2H), 7.50 (d, J=7.58 Hz, 1H), 6.80(ddd, J=7.07, 10.36, 16.93 Hz, 1H), 6.14-6.26 (m, 1H), 6.14-6.26 (m,1H), 5.70-5.77 (m, 1H), 4.27-4.60 (m, 1H), 3.93-4.23 (m, 2H), 3.12-3.26(m, 1H), 2.85-2.97 (m, 1H), 2.04-2.12 (m, 1H), 1.84-1.93 (m, 1H),1.67-1.81 (m, 1H), 1.53-1.64 (m, 1H).

Example 420:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(1-benzyl-1H-pyrazol-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-(1-benzyl-1H-pyrazol-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a 2-5 mL Biotage microwave vial with a stir bar were added1-benzyl-1H-pyrazol-3-amine (132.7 mg, 0.766 mmol),2-chloro-4-iodonicotinonitrile (201 mg, 0.760 mmol), Pd(OAc)₂ (3.7 mg,0.017 mmol), DPEPhos (12.5 mg, 0.0232 mmol), and Cs₂CO₃ (344 mg, 1.06mmol). The vial was sealed, treated with dioxane (1.52 mL),evacuated/flushed with argon 4×, and stirred at 150° C. under argon for30. The reaction was then cooled to room temp, treated with tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate22) (1.2 mL, 0.65 M, 0.78 mmol) via syringe, evacuated/flushed withargon 4×, and stirred at 150° C. for 15 min. The reaction was thencooled to room temperature, treated with solid CDI (492.6 mg, 3.038mmol) in one portion under air, resealed and evacuated/flushed withargon 4×, and stirred at 150° C. for 15 min. The reaction was dilutedwith EtOAc (10 mL), and washed with 0.5 M citric acid/brine (2×8 mL) and2 M K₂CO₃ (1×5 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The reaction mixture was purified by normalphase flash column chromatography (SiO₂) to give the title compound asan orange-yellow foam (256.6 mg, 58.85% yield).

Step B:(R)-5-(1-benzyl-1H-pyrazol-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(1-benzyl-1H-pyrazol-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(251.9 mg, 0.4390 mmol) in dioxane (2.2 mL) was treated with HCl (3.97 Min dioxane, 2.8 mL, 11 mmol) in one portion at room temperature, and theresulting mixture was stirred at room temperature for 1 h. The reactionwas concentrated to dryness to give the title compound as a yellow-beigepowder (253.1 mg, 100.8% yield).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(1-benzyl-1H-pyrazol-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(1-benzyl-1H-pyrazol-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(90.9 mg, 0.159 mmol) in DCM (1.05 mL) was treated with triethylamine(66 μL, 0.48 mmol) at room temperature under air and the solution wasstirred at 0° C. under positive argon pressure while acryloyl chloride(13 μL, 0.16 mmol) was added dropwise over 50 sec and was stirred at 0°C. for 5 min. The reaction was quenched with 1 M NaH₂PO₄ (3 mL) andextracted with DCM (1×5 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby HPLC and the combined fractions were neutralized with a few drops of1M NaHCO₃ until pH>8, and concentrated to dryness. The residue waspartitioned with water (2 mL) and DCM (4 mL), and the organic layer wasdried over anhydrous Na₂SO₄, filtered, and concentrated to dryness togive the title compound as a yellow film (24.5 mg, 29.2% yield). MS(ESI): mass calcd. for C₂₇H₂₅N₇O₃S, 527.2; m/z found, 528.3 [M+H]+. 1HNMR (400 MHz, CDCl3) δ 9.46 (br s, 1H), 8.36 (d, J=5.93 Hz, 1H), 7.53(s, 1H), 7.28-7.43 (m, 5H), 6.53-6.71 (m, 1H), 6.27-6.45 (m, 3H),5.69-5.90 (m, 1H), 5.52-5.69 (m, 1H), 5.35 (s, 2H), 3.84-4.26 (m, 3H),3.42-3.80 (m, 1H), 3.18-3.40 (m, 1H), 1.98-2.14 (m, 1H), 1.63-1.86 (m,3H).

Example 421:(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-([1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a 2-5 mL Biotage microwave vial with a stir bar were added3-aminobiphenyl (370.5 mg, 2.189 mmol), 2-chloro-4-iodonicotinonitrile(578 mg, 2.186 mmol), Pd(OAc)₂ (9.6 mg, 0.043 mmol), DPEPhos (36.1 mg,0.0671 mmol), and Cs₂CO₃ (988 mg, 3.03 mmol). The vial was sealed andtreated with dioxane (4.35 mL), evacuated/flushed with argon 4×, andstirred at 150° C. under argon for 30. The reaction was then cooled toroom temperature, treated with tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate22) in dioxane (4.05 mL, 0.65 M, 2.63 mmol) via syringe,evacuated/flushed with argon 4×, and stirred at 150° C. for 15 min. Thereaction was then cooled to room temperature, treated with solid CDI(1.409 g, 8.689 mmol) in one portion under air, resealed andevacuated/flushed with argon 4×, and stirred at 150° C. for 15 min. Thereaction was diluted with EtOAc (10 mL), and washed with 0.5 M citricacid/brine (2×8 mL) and 2 M K₂CO₃ (1×5 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness. The reaction mixture was purifiedby flash column chromatography to give the title compound as a beigefoam (289 mg, 23.2% yield).

Step B:(R)-5-([1,1′-Biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-([1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(283.8 mg, 0.498 mmol) in dioxane (2.5 mL) was treated with HCl (3.97 Min dioxane, 6.3 mL, 25 mmol) in one portion at room temperature, and theresulting mixture was stirred at room temperature for 1 h. The reactionwas concentrated to dryness to give the title compound as a beige powder(290.4 mg, 102.7% yield).

Step C:(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-([1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(99.94 mg, 0.176 mmol) in DCM (1.2 mL) was treated with triethylamine(73 μL, 0.53 mmol) at room temperature under air, and the resulting wasstirred at 0° C. under positive argon pressure while acryloyl chloride(14.3 μL, 0.176 mmol) was added dropwise over 50 sec. The solution wasstirred at 0° C. for 5 min and was quenched with 1 M NaH₂PO₄ (3 mL) andextracted with DCM (1×5 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby HPLC to give the title compound (23.8 mg, 21.2% yield). MS (ESI):mass calcd. for C₂₉H₂₅N₅O₃S, 523.2; m/z found, 524.1 [M+H]+. 1H NMR (400MHz, MeOH-d4) δ 8.33 (d, J=5.56 Hz, 1H), 7.83 (d, J=8.59 Hz, 1H),7.62-7.77 (m, 4H), 7.32-7.50 (m, 1H), 7.32-7.50 (m, 1H), 7.32-7.50 (m,2H), 6.80 (ddd, J=6.06, 10.61, 16.67 Hz, 1H), 6.17-6.24 (m, 2H),5.70-5.75 (m, 1H), 4.25-4.59 (m, 1H), 3.90-4.23 (m, 2H), 3.19 (br dd,J=9.35, 12.88 Hz, 1H), 2.82-2.98 (m, 1H), 2.02-2.13 (m, 1H), 1.87 (td,J=3.66, 13.39 Hz, 1H), 1.68-1.81 (m, 1H), 1.53-1.63 (m, J=8.60 Hz, 1H).

Example 422:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-benzylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described insteps A-C in Example 421, and using 4-benzylaniline in place of3-aminobiphenyl in step A to yield the title compound. MS (ESI): masscalcd. for C₃₀H₂₇N₅O₃S, 537.2; m/z found, 538.0 [M+H]+. 1H NMR (400 MHz,CDCl3) δ 9.46 (br s, 1H), 8.32 (br d, J=4.55 Hz, 1H), 7.31-7.41 (m, 4H),7.22-7.25 (m, 4H), 6.57-6.68 (m, 1H), 6.21-6.48 (m, 2H), 6.11 (br s,1H), 5.70-5.80 (m, 1H), 5.56 (br s, 1H), 3.94-4.10 (m, 4H), 3.28-3.78(m, 3H), 2.04 (br d, J=14.15 Hz, 1H), 1.95 (br s, 1H), 1.69 (br s, 2H).

Example 423:(R)-5-([1,1′-Biphenyl]-4-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described insteps A-C in Example 421, and using 4-aminobiphenyl in place of3-aminobiphenyl in step A to yield the title compound. MS (ESI): masscalcd. for C₂₉H₂₅N₅O₃S, 523.2; m/z found, 524.3 [M+H]+. 1H NMR (400 MHz,MeOH-d4) δ 8.34 (d, J=5.6 Hz, 1H), 7.87 (d, J=8.6 Hz, 2H), 7.70 (d,J=7.1 Hz, 2H), 7.44-7.57 (m, 4H), 7.35-7.44 (m, 1H), 6.73-6.88 (m, 1H),6.25 (d, J=6.1 Hz, 1H), 6.21 (d, J=16.7 Hz, 1H), 5.70-5.80 (m, 1H),4.60-4.27 (m, 1H), 4.17-4.03 (m, 1H), 3.89-3.99 (m, 1H), 3.09-3.24 (m,1H), 2.90 (m, 1H), 2.06 (br. s., 1H), 1.83-1.93 (m, 1H), 1.74 (br. s.,1H), 1.60 (br. s., 1H).

Example 424:(R)—N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a 100 mL flask containing4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride (Intermediate 40, 1.046 g, 2.479 mmol) in THF (10 mL) was addedwith stirring triethylamine (10.0 mL, 123 mmol),(R)-1-Boc-3-aminopiperidine (768 mg, 3.72 mmol), and THF (10 mL) and wasstirred for 15 hours. The reaction was quenched by pouring into aseparatory funnel containing aqueous saturated NaHCO₃ and was extractedinto ether and dried over anhydrous MgSO₄. The mixture was filtered andconcentrated to dryness to give the title compound as a dark red solid(1.26 g, 86.8% yield).

Step B:(R)—N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To an oven dried microwave vial were added(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860) (113 mg, 0.216 mmol), N,N-dimethylglycine (44.9 mg, 0.435mmol), THF (3 mL), HATU (168 mg, 0.442 mmol), and triethylamine (2.0 mL,14 mmol) and was capped and warmed in the microwave for 30 sec at 100°C. The reaction was concentrated to dryness and filtered through syringefilter. The residue was purified by HPLC to give the title compound(36.3 mg, 29.4% yield). MS (ESI): mass calcd. for C₃₀H₃₀N₆O₄S, 570.7;m/z found, 571.1 [M+H]⁺. 1H NMR (500 MHz, Methanol-d4) δ 8.52 (s, OH),8.34-8.23 (m, 1H), 7.48-7.34 (m, 4H), 7.24-7.07 (m, 5H), 6.21-6.13 (m,1H), 4.54-3.64 (m, 5H), 3.20-3.06 (m, 1H), 3.06-2.84 (m, 1H), 2.68-2.55(m, 6H), 2.15-1.97 (m, 1H), 1.97-1.48 (m, 3H).

Example 425:(R)—N-(1-(2-(Dimethylamino)acetyl)pyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described insteps A-C in Example 424, and using (R)-1-Boc-3-aminopyrrolidine andDIEA in place of (R)-1-Boc-3-aminopiperidine and triethylamine in step Ato yield the title compound. MS (ESI): mass calcd. for C₂₉H₂₈N₆O₄S,556.6; m/z found, 557.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 8.45-8.32 (m,1H), 7.44-7.33 (m, 2H), 7.33-7.25 (m, 1H), 7.24-7.08 (m, 5H), 6.27 (dd,J=29.7, 6.7 Hz, 1H), 6.20-6.10 (m, 1H), 4.72-4.60 (m, 1H), 3.86-3.53 (m,4H), 3.40 (dd, J=14.4, 8.6 Hz, 1H), 3.16 (dd, J=46.1, 14.4 Hz, 1H),2.56-2.48 (m, 6H), 2.43-2.14 (m, 1H), 2.09-1.91 (m, OH).

Example 426:(R)-5-([1,1′-Biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described insteps A-B in Example 421. MS (ESI): mass calcd. for C₂₆H₂₃N₅O₂S, 469.2;m/z found, 470.2 [M+H]+. 1H NMR (400 MHz, 95:5 CDCl3/MeOH-d4) δ 8.31 (d,J=5.6 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.61 (d,J=7.1 Hz, 2H), 7.57 (d, J=2.0 Hz, 1H), 7.46 (t, J=7.3 Hz, 2H), 7.36-7.42(m, 1H), 7.30-7.35 (m, 1H), 6.18 (d, J=5.6 Hz, 1H), 4.11 (dt, J=7.1, 3.5Hz, 1H), 3.12 (dd, J=12.4, 3.3 Hz, 1H), 2.83-2.91 (m, 1H), 2.66-2.82 (m,2H), 1.92 (td, J=8.1, 4.0 Hz, 1H), 1.65-1.85 (m, 2H), 1.60 (td, J=8.6,4.0 Hz, 1H)

Example 427:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(benzo[b]thiophen-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described insteps A-C in Example 421, and using benzo[b]thiophen-2-amine in place of3-aminobiphenyl in step A to yield the title compound. MS (ESI): masscalcd. for C₂₅H₂₁N₅O₃S₂, 503.1; m/z found, 504.1 [M+H]+. 1H NMR (400MHz, CDCl3) δ 9.59 (br. s., 1H), 8.31-8.45 (m, 1H), 7.75-7.90 (m, 2H),7.41-7.47 (m, 2H), 7.40 (s, 1H), 6.54-6.71 (m, 1H), 6.41 (br. s., 2H),6.31 (d, J=16.7 Hz, 1H), 5.65-5.82 (m, 1H), 4.13 (br. s., 1H), 4.02 (d,J=13.1 Hz, 2H), 3.80 (br. s., 1H), 3.55 (br. s., 1H), 3.29 (br. s., 1H),2.05 (br. s., 1H), 1.98 (br. s., 1H), 1.60-1.71 (m, 1H).

Example 428:(R)-5-(Benzo[b]thiophen-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described insteps A-B in Example 421, and using benzo[b]thiophen-2-amine in place of3-aminobiphenyl in step A to yield the title compound. MS (ESI): masscalcd. for C₂₂H₁₉N₅O₂S₂, 449.1; m/z found, 450.1 [M+H]+. 1H NMR (400MHz, MeOH-d4) δ 8.19 (d, J=6.1 Hz, 1H), 7.82-7.93 (m, 2H), 7.45 (s, 1H),7.38-7.44 (m, 2H), 6.28 (d, J=5.6 Hz, 1H), 4.10-4.24 (m, 1H), 3.06-3.16(m, 1H), 2.81-3.00 (m, 2H), 1.91-2.10 (m, 2H), 1.66-1.83 (m, 2H),1.24-1.44 (m, 1H).

Example 429:(R)-5-(Naphthalen-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described insteps A-B in Example 421, and using 2-aminonaphthalene in place of3-aminobiphenyl in step A to yield the title compound. MS (ESI): masscalcd. for C₂₄H₂₁N₅O₂S, 443.1; m/z found, 444.1 [M+H]+. 1H NMR (400 MHz,MeOH-d4) δ 8.47 (d, J=6.57 Hz, 1H), 8.16 (d, J=9.09 Hz, 1H), 8.01-8.07(m, 2H), 7.98 (d, J=7.58 Hz, 1H), 7.58-7.69 (m, 2H), 7.52 (dd, J=2.02,8.59 Hz, 1H), 6.43 (d, J=6.57 Hz, 1H), 4.26-4.37 (m, 1H), 3.52-3.58 (m,1H), 3.33-3.40 (m, 1H), 2.96-3.05 (m, 2H), 2.05-2.16 (m, 2H), 1.74-1.93(m, 2H).

Example 430:(R)-5-(4-Benzylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described insteps A-B in Example 421, and using 4-benzylaniline in place of3-aminobiphenyl in step A to yield the title compound. MS (ESI): masscalcd. for C24H23N7O2S, 483.2; m/z found, 484.2 [M+H]+. 1H NMR (400 MHz,MeOH-d4) δ 8.45 (d, J=6.57 Hz, 1H), 7.46-7.53 (m, J=8.08 Hz, 2H),7.34-7.40 (m, J=8.59 Hz, 2H), 7.24-7.34 (m, 4H), 7.17-7.24 (m, 1H), 6.37(d, J=6.06 Hz, 1H), 4.23-4.34 (m, 1H), 4.10 (s, 2H), 3.54 (dd, J=4.29,11.87 Hz, 1H), 3.33-3.39 (m, 1H), 2.92-3.03 (m, 2H), 2.04-2.15 (m, 2H),1.70-1.92 (m, 2H).

Example 431:(R)-5-(1-Benzyl-1H-pyrazol-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described insteps A-B in Example 421, and using 1-benzyl-1H-pyrazol-3-amine in placeof 3-aminobiphenyl in step A to yield the title compound. MS (ESI): masscalcd. for C24H23N7O2S, 473.2; m/z found, 474.1 [M+H]+. 1H NMR (400 MHz,MeOH-d4) δ 8.53 (d, J=6.57 Hz, 1H), 7.95 (d, J=2.53 Hz, 1H), 7.28-7.41(m, 5H), 6.60 (d, J=6.57 Hz, 1H), 6.50 (d, J=2.53 Hz, 1H), 5.43 (s, 2H),4.23-4.35 (m, 1H), 3.53 (dd, J=4.04, 12.13 Hz, 1H), 3.32-3.39 (m, 1H),2.93-3.04 (m, 2H), 2.04-2.13 (m, 2H), 1.71-1.93 (m, 2H).

Example 432:5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-((4*S)-2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on5-(2-methyl-4-phenoxyphenyl)-N-(2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 258, 841.57 mg) via chiral SFC (Stationary phase: CHIRALCELOD-H 5 m 250×20 mm, Mobile phase: 55% CO₂, 45% iPOH (0.3% iPrNH₂)) and asecond purification was performed via chiral SFC (Stationary phase:Whelk 01 (S,S) 5 μm 250×21.1 mm, Mobile phase: 45% CO₂, 55% MeOH (0.3%iPrNH₂)) to give the title compound (as the *S atropisomer; 15 mg). MS(ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.6; m/z found, 513.2 [M+H]+. 1HNMR (600 MHz, Chloroform-d) δ 8.35 (d, J=5.4 Hz, 1H), 7.48-7.35 (m, 2H),7.22-6.91 (m, 6H), 6.02 (d, J=5.5 Hz, 1H), 5.58 (d, J=8.0 Hz, 1H),4.09-3.96 (m, 1H), 3.39-2.68 (m, 3H), 2.18-1.96 (m, 6H), 1.47-1.20 (m,2H), 1.13-1.00 (m, 3H).

Example 433:5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-((4*S)-2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on5-(2-methyl-4-phenoxyphenyl)-N-(2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 258, 841.57 mg) via chiral SFC (Stationary phase: CHIRALCELOD-H 5 m 250×20 mm, Mobile phase: 55% CO₂, 45% iPOH (0.3% iPrNH₂)) and asecond purification was performed via chiral SFC (Stationary phase:Whelk O1 (S,S) 5 m 250×21.1 mm, Mobile phase: 45% CO₂, 55% MeOH (0.3%iPrNH₂)) to give the title compound (as the *R atropisomer; 17 mg). MS(ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.6; m/z found, 513.2 [M+H]+. ¹HNMR (600 MHz, CDCl₃): δ 8.36 (d, J=5.5 Hz, 1H), 7.48-7.33 (m, 2H),7.23-6.93 (m, 7H), 6.02 (d, J=5.5 Hz, 1H), 5.52-5.41 (m, 1H), 4.08-3.95(m, 1H), 3.21-3.13 (m, 1H), 2.92-2.75 (m, 2H), 2.13 (s, 3H), 2.10-1.98(m, 2H), 1.44-1.32 (m, 1H), 1.30-1.22 (m, 1H), 1.14-1.03 (m, 4H).

Example 434:5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-((4*R)-2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on5-(2-methyl-4-phenoxyphenyl)-N-(2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 258) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5 m250×20 mm, Mobile phase: 55% CO₂, 45% iPOH (0.3% iPrNH₂)) to give thetitle compound (as the *S atropisomer). MS (ESI): mass calcd. forC₂₈H₂₇N₅O₃S, 513.6; m/z found, 513.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): δ8.35 (s, 1H), 7.47-7.34 (m, 2H), 7.23-6.89 (m, 6H), 6.16 (s, 1H), 6.01(d, J=5.4 Hz, 1H), 4.21-4.04 (m, 1H), 3.41-3.20 (m, 1H), 3.03-2.78 (m,2H), 2.13 (s, 4H), 1.69 (s, 1H), 1.46-1.22 (m, 7H).

Example 435:5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-((4*R)-2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on5-(2-methyl-4-phenoxyphenyl)-N-(2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 258, 841.57) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5m 250×20 mm, Mobile phase: 55% CO₂, 45% iPOH (0.3% iPrNH₂)) to give thetitle compound (as the *R atropisomer; 12 mg). MS (ESI): mass calcd. forC₂₈H₂₇N₅O₃S, 513.6; m/z found, 513.2 [M+H]⁺. 1H NMR (600 MHz,Chloroform-d) δ 8.31 (s, 1H), 7.40-7.36 (m, 2H), 7.32 (s, 1H), 7.20-7.15(m, 2H), 7.11-7.06 (m, 2H), 6.99 (d, J=2.8 Hz, 1H), 6.94 (dd, J=8.5, 2.8Hz, 1H), 5.98 (d, J=5.4 Hz, 1H), 4.26 (s, 1H), 3.67 (s, 1H), 3.54 (s,1H), 3.38 (d, J=24.9 Hz, 1H), 3.10 (s, 1H), 2.21 (s, 2H), 2.11 (s, 3H),1.95 (d, J=13.2 Hz, 1H), 1.54 (d, J=6.2 Hz, 3H), 1.25 (s, 2H).

Example 436:N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using (4-aminotetrahydropyran-4-yl)methanol inplace of tert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate instep G to yield the title compound.

Step B:N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed onN-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(869 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5 m 250×20 mm,Mobile phase: 50% CO₂, 50% iPrOH) to give the title compound (as the *Satropisomer; 17 mg). MS (ESI): mass calcd. for C₂₈H₂₆N₄O₅S, 530.6; m/zfound, 530.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): δ 9.65 (s, 1H), 8.32 (d,J=5.5 Hz, 1H), 7.44-7.35 (m, 2H), 7.25-7.16 (m, 2H), 7.14-7.08 (m, 2H),7.03-6.92 (m, 2H), 6.00 (d, J=5.4 Hz, 1H), 5.54 (s, 1H), 4.49 (s, 1H),3.99 (d, J=11.7 Hz, 1H), 3.87-3.76 (m, 3H), 3.76-3.67 (m, 2H), 2.14-2.00(m, 5H), 1.95-1.81 (m, 2H).

Example 437:N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using (4-aminotetrahydropyran-4-yl)methanol inplace of tert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate instep G to yield the title compound.

Step B:N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed onN-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(869 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5 m 250×20 mm,Mobile phase: 50% CO₂, 50% iPrOH) to give the title compound (as the *Ratropisomer; 19 mg). MS (ESI): mass calcd. for C₂₈H₂₆N₄O₅S, 530.6; m/zfound, 530.2 [M+H]⁺. 1H NMR (600 MHz, Chloroform-d) δ 9.59 (s, 1H), 8.33(d, J=5.5 Hz, 1H), 7.49-7.34 (m, 2H), 7.24-7.17 (m, 2H), 7.13-7.09 (m,2H), 7.02-6.96 (m, 2H), 6.01 (d, J=5.5 Hz, 1H), 5.52 (s, 1H), 4.43 (s,1H), 4.00-3.93 (m, 1H), 3.88-3.79 (m, 3H), 3.71 (ddt, J=12.3, 9.3, 3.2Hz, 2H), 2.13-2.10 (m, 3H), 1.96-1.87 (m, 2H), 1.23-1.19 (m, 2H).

Example 438:(R)—N-(1-(2-Chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R)—N-(1-(2-chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 260) via chiral SFC (Stationary phase: CHIRALCEL OJ-H 5 μm250×20 mm, Mobile phase: 70% CO₂, 30% EtOH) to give the title compound(as the *S atropisomer; 39 mg). MS (ESI): mass calcd. for C₃₂H₃₀ClN₅O₄S,616.1; m/z found, 615.2 [M+H]⁺. 1H NMR (600 MHz, Chloroform-d) δ 9.50(s, 1H), 8.48-8.27 (m, 1H), 7.48-7.33 (m, 2H), 7.23-7.14 (m, 2H),7.14-7.07 (m, 2H), 7.05-6.99 (m, 1H), 6.99-6.92 (m, 1H), 6.12-6.06 (m,1H), 6.06-5.99 (m, 1H), 5.89 (s, 1H), 4.23-4.11 (m, 1H), 4.01-3.81 (m,1H), 3.81-3.68 (m, 1H), 3.50-3.45 (m, 1H), 3.32-3.20 (m, 1H), 2.14 (s,4H), 2.07-1.94 (m, 2H), 1.89-1.82 (m, 4H), 1.78-1.63 (m, 2H).

Example 439:(R)—N-(1-(2-Chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R)—N-(1-(2-chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 260) via chiral SFC (Stationary phase: CHIRALCEL OJ-H 5 μm250×20 mm, Mobile phase: 70% CO₂, 30% EtOH) to give the title compound(as the *R atropisomer; 39 mg). MS (ESI): mass calcd. for C₃₂H₃₀ClN₅O₄S,616.1; m/z found, 615.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): δ 9.51 (s, 1H),8.47-8.25 (m, 1H), 7.51-7.32 (m, 2H), 7.24-6.91 (m, 6H), 6.22-5.82 (m,2H), 4.28-4.06 (m, 1H), 3.97-3.64 (m, 2H), 3.57-3.23 (m, 2H), 2.17-2.09(m, 3H), 2.08-1.92 (m, 2H), 1.92-1.90 (m, 3H), 1.88-1.84 (m, 3H),1.81-1.63 (m, 2H).

Example 440:(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a small oven dried microwave vial under Ar were added(R)-4-Oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbo(Example 91120 mm, 0 mg, 0.424 mmol), trans-4-dimethylaminocrotonic acidhydrochloride (151.3 mg, 0.9140 mmol), THF (6 mL), HATU (481.3 mg, 1.266mmol), and triethylamine (0.8 m, 6 mmol) and the vial was capped and washeated in the microwave for 30 seconds at 100° C. The reaction mixturewas concentrated to dryness and purified by flash column chromatographyand then by HPLC to give the title compound (65 mg, 26% yield). MS(ESI): mass calcd. for C₃₁H₃₀N₆O₄S, 582.7; m/z found, 583.2 [M+H]⁺. 1HNMR (400 MHz, DMSO-d6) δ 8.49-8.24 (m, 2H), 7.56-7.36 (m, 4H), 7.29-7.05(m, 6H), 6.75-6.54 (m, 1H), 6.50-6.31 (m, 1H), 6.07 (d, J=5.5 Hz, 1H),4.62-4.34 (m, 1H), 3.95-3.56 (m, 4H), 3.18-3.01 (m, 2H), 2.29-1.84 (m,8H).

Example 441:(R)—N-(1-Acryloylpyrrolidin-3-yl)-N-methyl-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A purification was performed on(R)—N-(1-acryloylpyrrolidin-3-yl)-N-methyl-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 137, 907 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H 5μm 250×20 mm, Mobile phase: 60% CO₂, 40% MeOH) to give the titlecompound (as the *S atropisomer; 30 mg). MS (ESI): mass calcd. forC₃₀H₂₇N₅O₄S, 553.6; m/z found, 553.2 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) δ 9.79 (s, 1H), 8.51-8.24 (m, 1H), 7.47-7.34 (m, 2H),7.24-7.04 (m, 4H), 7.06-6.88 (m, 2H), 6.54-6.36 (m, 2H), 6.11-5.97 (m,1H), 5.80-5.66 (m, 1H), 5.37-5.16 (m, 1H), 4.08-3.73 (m, 2H), 3.72-3.40(m, 2H), 3.24 (d, J=16.6 Hz, 3H), 2.32 (s, 1H), 2.26-2.02 (m, 4H).

Example 442:(R)—N-(1-Acryloylpyrrolidin-3-yl)-N-methyl-5-(*R)-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A purification was performed on(R)—N-(1-acryloylpyrrolidin-3-yl)-N-methyl-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 137, 907 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H 5μm 250×20 mm, Mobile phase: 60% CO₂, 40% MeOH) to give the titlecompound (as the *R atropisomer; 29 mg). MS (ESI): mass calcd. forC₃₀H₂₇N₅O₄S, 553.6; m/z found, 553.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ9.80 (s, 1H), 8.43-8.29 (m, 1H), 7.46-7.34 (m, 2H), 7.24-7.07 (m, 4H),7.05-6.90 (m, 2H), 6.51-6.33 (m, 2H), 6.13-5.95 (m, 1H), 5.83-5.63 (m,1H), 5.36-5.17 (m, 1H), 4.02-3.73 (m, 2H), 3.73-3.44 (m, 2H), 3.25 (d,J=13.9 Hz, 3H), 2.39-2.16 (m, 2H), 2.13 (s, 3H).

Example 443:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using 4-fluoronitrobenzene in place of5-fluoro-2-nitrotoluene in step A and using(R)-(+)-1-Boc-3-aminopyrrolidine in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G to yield thetitle compound. MS (ESI): mass calcd. for C₂₈H₂₃N₅O₄S, 525.6; m/z found,526.2 [M+H]⁺. 1H NMR (500 MHz, Methanol-d4) δ 8.31 (d, J=6.0 Hz, 1H),7.44-7.37 (m, 4H), 7.21-7.16 (m, 3H), 7.11 (d, J=7.7 Hz, 2H), 6.68-6.56(m, 1H), 6.32-6.25 (m, 1H), 6.18 (d, J=5.0 Hz, 1H), 5.79-5.72 (m, 1H),4.70-4.59 (m, 1H), 4.05-3.98 (m, 0.5H), 3.91-3.82 (m, 1H), 3.77-3.70 (m,1H), 3.64-3.57 (m, 1H), 3.55-3.49 (m, 0.5H), 2.40-2.23 (m, 1H),2.21-2.06 (m, 1H).

Example 444:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 4-isopropyl-2-methyl-aniline (Intermediate7) in place of 2-methyl-4-phenoxy-aniline in step C and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G to yield thetitle compound. MS (ESI): mass calcd. for C₂₇H₂₉N₅O₃S, 503.6; m/z found,540.7 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33-8.25 (m, 1H), 7.35-7.31(m, 1H), 7.30-7.25 (m, 1H), 7.24-7.19 (m, 1H), 6.84-6.72 (m, 1H),6.23-6.15 (m, 1H), 6.00-5.95 (m, 1H), 5.77-5.69 (m, 1H), 4.56-4.25 (m,1H), 4.20-3.90 (m, 2H), 3.25-3.11 (m, 1H), 2.99-2.46. (m, 2H), 2.17-2.10(m, 3H), 2.09-2.03 (m, 1H), 1.94-1.81 (m, 1H), 1.76-1.59 (m, 2H),1.30-0.99 (m, 6H).

Example 445:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-isopropyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-G in Example 1, and using 4-isopropyl-2-methyl-aniline (Intermediate7) in place of 2-methyl-4-phenoxy-aniline in step C and using1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate 5) in placeof tert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in stepG to yield the title compound. MS (ESI): mass calcd. for C₂₆H₂₇N₅O₃S,489.6; m/z found, 490.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33-8.25 (m,1H), 7.35-7.31 (m, 1H), 7.30-7.25 (m, 1H), 7.24-7.19 (m, 1H), 6.67-6.52(m, 1H), 6.31-6.21 (m, 1H), 6.00-5.95 (m, 1H), 5.77-5.69 (m, 1H),4.67-4.58 (m, 1H), 4.03-3.66 (m, 3H), 3.61-3.48 (m, 1H), 3.00-2.64 (m,1H), 2.36-2.22 (m, 1H), 2.17-2.10 (m, 3H), 2.08-1.65 (m, 1H), 1.30-0.96(m, 6H).

Example 446:(R)-5-(4-Isopropyl-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using benzofuran-7-ol (Intermediate 8) in place of2-methyl-4-phenoxy-aniline in step C and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G to yield thetitle compound. MS (ESI): mass calcd. for C₂₄H₂₇N₅O₂S, 449.6; m/z found,450.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35-8.28 (m, 1H), 7.35-7.31(m, 1H), 7.30-7.25 (m, 1H), 7.24-7.19 (m, 1H), 6.00-5.95 (m, 1H),4.55-4.25 (m, 1H), 3.85-3.50 (m, 1H), 3.40-3.33 (m, 1H), 3.00-249. (m,3H), 2.17-2.10 (m, 3H), 2.08-1.99 (m, 2H), 1.83-1.68 (m, 2H), 1.30-0.96(m, 6H).

Example 447:(R)-5-(4-Isopropyl-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-isopropyl-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 446, 40 mg, 0.089 mmol) in DCM (2 mL) were added formaldehyde(1.0 mL, 37 wt. % in H₂O), and NaBH(OAc)₃ (40 mg, 0.19 mmol) and wasreacted at rt for 20 min. The reaction mixture was concentrated todryness and the residue was purified by flash column chromatography andpreparative TLC to give the title compound as a yellow solid (35 mg). MS(ESI): mass calcd. for C₂₅H₂₉N₅O₂S, 463.6; m/z found, 464.2 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.35-8.28 (m, 1H), 7.35-7.31 (m, 1H), 7.30-7.25(m, 1H), 7.24-7.19 (m, 1H), 6.00-5.95 (m, 1H), 4.41-4.19 (m, 1H),3.67-3.52 (m, 1H), 3.46-3.35 (m, 1H), 3.02-2.94. (m, 2H), 2.89 (s, 3H),2.74-2.43 (m, 1H), 2.17-2.10 (m, 3H), 2.08-2.03 (m, 2H), 1.90-1.71 (m,2H), 1.30-0.96 (m, 6H).

Example 448:(R,*Z)—N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*)-(2methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R,ZE)-N-(1-(2-cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 40; 55.5 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5μm 250×20 mm, Mobile phase: 50% CO₂, 50% EtOH) and a second purification(25 mg from fraction 3, first purification) was performed via chiral SFC(Stationary phase: CHIRALCEL OJ-H 5 μm 250×20 mm, Mobile phase: 75% CO₂,25% MeOH) to give the title compound (as the *S atropisomer and as the*Z configuration; 7 mg). MS (ESI): mass calcd. for C₃₅H₃₄N₆O₅S, 650.8;m/z found, 650.2 [M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.51-8.24 (m,1H), 7.49-7.35 (m, 2H), 7.35-7.25 (m, 1H), 7.25-6.92 (m, 5H), 6.73 (d,J=1.5 Hz, 1H), 6.15-5.94 (m, 1H), 4.69-4.27 (m, 1H), 4.20-3.74 (m, 2H),3.27-3.23 (m, 2H), 3.21-2.72 (m, 2H), 2.21-2.07 (m, 3H), 1.95-1.70 (m,2H), 1.44-1.28 (m, 8H), 1.15-0.70 (m, 1H).

Example 449:(R,*Z)—N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R,EZ)—N-(1-(2-cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 40; 55.5 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5μm 250×20 mm, Mobile phase: 50% CO₂, 50% EtOH) and a second purification(25 mg from fraction 3, first purification) was performed via chiral SFC(Stationary phase: CHIRALCEL OJ-H 5 μm 250×20 mm, Mobile phase: 75% CO₂,25% MeOH) to give the title compound (as the *R atropisomer and as the*Z configuration; 16 mg). MS (ESI): mass calcd. for C₃₅H₃₄N₆O₅S, 650.8;m/z found, 650.2 [M+H]⁺. 1H NMR (400 MHz, Methanol-d4) δ 8.32 (d, J=5.6Hz, 1H), 7.46-7.34 (m, 2H), 7.32 (d, J=8.6 Hz, 1H), 7.25-7.14 (m, 1H),7.14-7.03 (m, 3H), 1.38-1.34 (m, 1H), 6.98 (dd, J=8.6, 2.8 Hz, 1H),6.95-6.82 (m, 1H), 6.07 (d, J=5.6 Hz, 1H), 4.54-3.36 (m, 3H), 3.29-2.74(m, 5H), 2.27-2.00 (m, 4H), 1.99-1.84 (m, 1H), 1.87-1.57 (m, 3H), 1.43(s, 6H).

Example 450:(R,*E)-N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R,EZ)—N-(1-(2-cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 40; 55.5 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5μm 250×20 mm, Mobile phase: 50% CO₂, 50% EtOH) and a second purification(25 mg from fraction 2, first purification) was performed via chiral SFC(Stationary phase: CHIRALCEL OJ-H 5 m 250×20 mm, Mobile phase: 75% CO₂,25% MeOH) to give the title compound (as the *S atropisomer and as the*E configuration; 6 mg). MS (ESI): mass calcd. for C₃₅H₃₄N₆O₅S, 650.8;m/z found, 650.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.39-8.28 (m, 1H),7.51-6.66 (m, 9H), 6.08 (d, J=5.5 Hz, 1H), 4.63-3.68 (m, 3H), 3.30-3.06(m, 4H), 3.01-2.64 (m, 1H), 2.23-2.01 (m, 3H), 1.96-1.83 (m, 1H),1.83-1.51 (m, 2H), 1.48-1.40 (m, 2H), 1.40-1.29 (m, 5H).

Example 451:(R,*E)-N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R,EZ)—N-(1-(2-cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 40; 55.5 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5m 250×20 mm, Mobile phase: 50% CO₂, 50% EtOH) and a second purification(25 mg from fraction 2, first purification) was performed via chiral SFC(Stationary phase: CHIRALCEL OJ-H 5 μm 250×20 mm, Mobile phase: 75% CO₂,25% MeOH) to give the title compound (as the *R atropisomer and as the*E configuration; 14 mg). MS (ESI): mass calcd. for C₃₅H₃₄N₆O₅S, 650.8;m/z found, 650.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34 (d, J=5.5 Hz,1H), 7.47-6.83 (m, 9H), 6.08 (d, J=5.6 Hz, 1H), 4.17-3.94 (m, 2H),3.30-3.28 (m, 3H), 3.22-2.82 (m, 1H), 2.19-2.02 (m, 4H), 2.00-1.86 (m,1H), 1.86-1.51 (m, 2H), 1.51-1.36 (m, 7H), 1.29 (s, 1H).

Example 452:N-((1-Acryloylpyrrolidin-3-yl)methyl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using 4-fluoronitrobenzene in place of5-fluoro-2-nitrotoluene in step A and using2-(aminomethyl)-1-N-Boc-pyrrolidine in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G to yield thetitle compound as an off-white solid. MS (ESI): mass calcd. forC29H25N5O4S, 539.6; m/z found, 540.1 [M+H]+. 1H NMR (400 MHz,Chloroform-d) δ 9.51 (s, 1H), 8.32 (d, J=5.6 Hz, 1H), 8.21 (t, J=4.4 Hz,1H), 7.39 (t, J=7.8 Hz, 2H), 7.30 (s, 1H), 7.15 (ddd, J=20.2, 13.2, 7.5Hz, 5H), 6.60-6.39 (m, 2H), 6.10 (d, J=5.5 Hz, 1H), 5.78 (dd, J=9.5, 2.9Hz, 1H), 4.53 (tt, J=6.9, 3.4 Hz, 1H), 3.73-3.58 (m, 3H), 3.40 (ddd,J=13.7, 10.1, 3.5 Hz, 1H), 2.06 (ddt, J=18.9, 15.0, 7.5 Hz, 4H), 1.85(td, J=6.0, 5.6, 2.5 Hz, 1H).

Example 453:4-Oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 4-fluoronitrobenzene in place of5-fluoro-2-nitrotoluene in step A and using2-(aminomethyl)-1-N-Boc-pyrrolidine in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G to yield thetitle compound as an off-white solid. MS (ESI): mass calcd. forC26H23N5O3S, 485.5; m/z found, 486.1 [M+H]+. 1H NMR (500 MHz,Chloroform-d) δ 9.68 (s, 1H), 9.50 (s, 2H), 8.42 (s, 1H), 8.17 (s, 1H),7.49 (dt, J=8.7, 2.9 Hz, 1H), 7.44-7.35 (m, 2H), 7.32 (dt, J=8.6, 2.6Hz, 1H), 7.22-7.05 (m, 3H), 6.04 (s, 1H), 4.39 (s, 1H), 3.95 (d, J=8.8Hz, 1H), 3.84-3.77 (m, 1H), 3.47 (d, J=19.5 Hz, 2H), 3.34 (s, 1H), 3.28(q, J=10.4, 8.3 Hz, 1H), 2.23-2.13 (m, 1H), 2.14-1.94 (m, 2H).

Example 454:(R)—N-(1-(1H-Imidazole-1-carbonyl)piperidin-3-yl)-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a 40 mL microwave vial were added 2-chloro-4-iodonicotinonitrile(1.451 g, 5.488 mmol), bis(2-diphenylphosphinophenyl)ether (90 mg, 0.17mmol), palladium(II) acetate (25 mg, 0.11 mmol), cesium carbonate (2.503g, 7.683 mmol), 2,2-difluoro-5-aminobenzodioxole (1.0 g, in 1.0 mLdioxane), and dioxane (10 mL) and was purged with N₂ stream for 30 min.The reaction was heated in the microwave at 150° C. for 30 min. To thereaction mixture was added tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate22) (8.44 mL, 5.49 mmol) and was purged with N₂ stream for 15 min. Thereaction was heated in microwave at 150° C. for 30 min. To the mixturewas added CDI (3.6 g, 22 mmol) and was heated at 150° C. for 30 min. Thereaction mixture was extracted with EtOAc and the organic phase waswashed with water and brine. The precipitate was filtered off throughCelite. The organic phase was over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The reaction mixture was purified by flashcolumn chromatography, then by HPLC to give the title compound as abrown solid (82.4 mg, 2.65% yield). MS (ESI): mass calcd. forC₂₅H₁₉F₂N₇O₅S, 567.5; m/z found, 568.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):δ 8.16-8.06 (m, 2H), 7.47 (s, 1H), 7.27-7.20 (m, 2H), 7.15-7.08 (m, 1H),7.06 (s, 1H), 6.80 (d, J=5.9 Hz, 1H), 5.16-5.06 (m, 1H), 4.17 (t, J=12.0Hz, 1H), 4.12-3.97 (m, 2H), 3.13 (t, J=12.4 Hz, 1H), 2.86-2.71 (m, 1H),1.92 (t, J=13.3 Hz, 2H), 1.83-1.72 (m, 1H).

Example 455:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methoxy-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-(4-methoxy-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a microwave vial with a stir bar were added2-chloro-4-iodonicotinonitrile (520 mg, 2.0 mmol),4-methoxy-3-(trifluoromethyl)aniline (369 mg, 1.93 mmol), DPEPhos (31mg, 0.058 mmol), Pd(OAc)₂ (9.9 mg, 0.044 mmol), and Cs₂CO₃ (924 mg, 2.84mmol). The vial was treated with dioxane (4 mL) via syringe, and theentire mixture was degassed under vacuum for 1 minute, and then ventedto nitrogen. The reaction mixture was heated in the microwave at 150° C.for 30 minutes. The reaction was then cooled to room temperature,treated with tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate22) (0.49 M in dioxane, 522 mg, 1.90 mmol) via syringe, evacuated andflushed with nitrogen, and stirred at 150° C. for 20 min. The reactionwas then cooled to room temperature. The reaction mixture was thentreated with solid CDI (1.195 g, 7.368 mmol) in one portion under air,resealed and evacuated and flushed with nitrogen, and stirred at 150° C.for 20 min. The reaction was diluted with EtOAc (100 mL) and saturatedaqueous sodium bicarbonate (100 mL), and the organic phase wascollected. The aqueous layer was extracted again with EtOAc (100 mL),and the combined organics were dried over anhydrous MgSO₄, concentratedto dryness, and purified by flash column chromatography to give thetitle compound (252 mg, 21.7% yield).

Step B:(R)-5-(4-Methoxy-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(4-methoxy-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(500 mg, 0.85 mmol) in dioxane (4 mL) was treated with 4 N HCl-dioxane(12 mL). After 30 min at room temperature, a gummy precipitate hadsettled on the bottom of the vial. The dioxane was poured off, and theprecipitate was treated with saturated aqueous sodium bicarbonate (20mL) and extracted with DCM (2×50 mL). The combined organic layers weredried over anhydrous MgSO₄ and concentrated to dryness. The resultingcrude product was purified by flash column chromatography to give thetitle compound as an off white solid (72 mg, 17% yield).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methoxy-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(4-methoxy-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(52 mg, 0.087 mmol) in DCM (5 mL) was stirred at room temperature andtriethylamine (36 μL, 0.26 mmol) was added via syringe, followed by veryslow addition of acryloyl chloride (7.0 μL, 0.086 mmol) 1 microliter ata time over 20 min. The suspension gradually became a homogeneoussolution. The reaction was closely monitored by LCMS, and when thestarting material peak was the same size as a new impurity peak that wasgrowing in, then the reaction mixture was quenched with saturatedaqueous sodium bicarbonate (10 mL). The mixture was treated with DCM (10mL), the mixture was extracted and the organic layer was separated. Theaqueous layer was extracted again with DCM, and the combined organicswere dried over anhydrous MgSO₄, and concentrated to dryness. Theresidue was purified by flash column chromatography to yield a productthat was dissolved in DCM (2 mL), which was then was treated withhexanes (10 mL). The resulting solid was isolated by filtration to givethe title compound as a tan solid (25 mg, 52% yield). MS (ESI): masscalcd. for C₂₅H₂₂F₃N₅O₄S, 545.5; m/z found, [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 10.24-10.12 (s, 1H), 8.39-8.26 (d, J=5.5 Hz, 1H), 8.14-8.02(m, 1H), 7.85-7.80 (d, J=2.4 Hz, 1H), 7.79-7.72 (m, 1H), 7.53-7.44 (d,J=8.9 Hz, 1H), 6.88-6.71 (m, 1H), 6.15-6.08 (d, J=16.9 Hz, 1H),6.07-6.03 (d, J=5.5 Hz, 1H), 5.73-5.63 (m, 1H), 4.53-4.15 (m, 1H),4.12-4.01 (m, 1H), 4.01-3.94 (s, 3H), 3.87-3.73 (m, 1H), 3.19-2.92 (m,1H), 2.83-2.61 (m, 1H), 2.00-1.90 (m, 1H), 1.84-1.58 (m, 2H), 1.52-1.36(m, 1H).

Example 456:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-cyclobutoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-cyclobutoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 605, 180 mg, 0.35 mmol) in DCM (1 mL) was added triethylamine(146 μL, 1.05 mmol). The mixture was cooled in an ice-water bath and toit was added acryloyl chloride (28 μL, 0.35 mmol) dropwise via syringe.The reaction mixture was stirred under air at 0° C. for 30 minutes. Thereaction mixture was partitioned between DCM (10 mL) and saturatedaqueous NaHCO₃ (10 mL). The aqueous phase was extracted once with EtOAc(10 mL) and the combined organic extracts were dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby flash column chromatography to give the title compound as a tanpowder (56.3 mg, 30.3% yield). MS (ESI): mass calcd. for C₂₈H₂₉N₅O₄S,531.6; m/z found, 532.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.45 (br. s.,1H), 8.34 (d, J=4.04 Hz, 1H), 7.06-7.14 (m, 1H), 6.83 (s, 1H), 6.79 (dd,J=2.02, 8.59 Hz, 1H), 6.57-6.69 (m, 1H), 6.28-6.48 (m, 1H), 6.17-6.28(m, 0.5H), 5.95-6.05 (m, 1H), 5.70-5.82 (m, 1H), 5.40-5.51 (m, 0.5H),4.67 (quin, J=7.07 Hz, 1H), 3.87-4.22 (m, 2.5H), 3.23-3.74 (m, 2.5H),2.42-2.54 (m, 2H), 1.99-2.28 (m, 6H), 1.61-1.99 (m, 5H).

Example 457:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-cyclobutoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, and using(R)-5-(4-Cyclobutoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 626) in place ofN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.MS (ESI): mass calcd. for C₂₇H₂₇N₅O₄S, 517.6; m/z found, 518.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): δ 9.45 (br. s., 1H), 8.35 (br. s., 1H), 7.21(d, J=8.59 Hz, 2H), 6.97 (d, J=8.59 Hz, 2H), 6.58-6.69 (m, 1H),6.27-6.50 (m, 1H), 6.18-6.26 (m, 0.5H), 6.08-6.18 (m, 1H), 5.69-5.82 (m,1H), 5.41-5.51 (m, 0.5H), 4.68 (quin, J=7.07 Hz, 1H), 3.87-4.21 (m, 2H),3.26-3.75 (m, 2H), 2.44-2.54 (m, 2H), 2.15-2.28 (m, 2H), 2.00-2.15 (m,1H), 1.62-1.99 (m, 6H).

Example 458:4-Oxo-N-(2-oxopiperidin-3-yl)-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 4-fluoronitrobenzene in place of5-fluoro-2-nitrotoluene in step A and using 3-aminopiperidin-2-one inplace of tert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate instep G to yield the title compound as an off-white solid. MS (ESI): masscalcd. for C26H21N5O4S, 499.5; m/z found, 500.2 [M+H]+. 1H NMR (500 MHz,Chloroform-d) δ 9.59 (s, 1H), 8.31 (d, J=5.5 Hz, 1H), 7.45-7.36 (m, 2H),7.34-7.25 (m, 2H), 7.23-7.07 (m, 5H), 7.03 (d, J=6.2 Hz, 1H), 6.40 (s,1H), 6.11 (d, J=5.5 Hz, 1H), 4.51 (dt, J=11.9, 6.1 Hz, 1H), 3.41 (ddd,J=8.5, 5.1, 2.3 Hz, 2H), 3.21 (q, J=7.3 Hz, 1H), 2.47 (dt, J=13.3, 5.1Hz, 1H), 2.05-1.90 (m, 1H), 1.88-1.74 (m, 1H).

Example 459:(R)-5-(4-Methoxy-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using steps A-B in Example 455, to yieldthe title compound as an off-white solid. MS (ESI): mass calcd. forC₂₂H₂₀F₃N₅O₃S, 491.5; m/z found, 492.0 [M+H]⁺. 1H NMR (600 MHz, MeOD) δ8.23 (d, J=5.6 Hz, 1H), 7.71-7.59 (m, 2H), 7.41 (d, J=8.7 Hz, 1H), 6.05(d, J=5.6 Hz, 1H), 4.22-4.11 (m, 1H), 4.02 (s, 3H), 3.31-3.28 (m, 1H),3.13-3.06 (m, 1H), 2.89-2.77 (m, 2H), 2.10-2.02 (m, 1H), 1.99-1.90 (m,1H), 1.79-1.68 (m, 2H).

Example 460:(R)-5-(3-Chloro-4-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-(3-chloro-4-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a 2-5 mL Biotage microwave vial with a stir bar were added3-chloro-4-methylaniline (69.3 mg, 0.489 mmol),2-chloro-4-iodonicotinonitrile (129 mg, 0.487 mmol), Pd(OAc)₂ (2.3 mg,0.010 mmol), DPEPhos (8.1 mg, 0.015 mmol), and Cs₂CO₃ (221 mg, 0.678mmol). The vial was sealed, treated with dioxane (0.98 mL), evacuatedand flushed with argon 4×, and stirred at 150° C. under argon for 30min. The reaction was cooled to room temperature and was treated withtert-butyl (3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate(Intermediate 22) (0.49 M in dioxane, 1.0 mL, 0.49 mmol) via syringe.The vial was sealed and evacuated and flushed with argon 4×, and stirredat 150° C. for 15 min. The reaction was then cooled to room temperature,treated with solid CDI (308 mg, 1.90 mmol) in one portion under air,resealed and evacuated and flushed with argon 4×, and stirred at 150° C.for 15 min. The reaction was diluted with EtOAc (10 mL), and washed with0.5 M citric acid and brine (2×8 mL) and 2 M K₂CO₃ (1×5 mL). The organicphase was dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was purified by normal phase flash columnchromatography (SiO₂) to give the title compound as an orange-yellowfoam (142.4 mg, 53.90% yield).

Step B:(R)-5-(3-Chloro-4-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(3-chloro-4-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(142.4 mg, 0.263 mmol) in dioxane (1.5 mL) was treated with HCl (3.97 Min dioxane, 3.5 mL, 14 mmol) in one portion at room temperature, and theresulting solution was stirred at room temperature for 1 h. The reactionwas concentrated to dryness to give the title compound as a yellow-beigepowder (118.1 mg, 92.27% yield). MS (ESI): mass calcd. forC21H20ClN₅O₂S, 441.1; m/z found, 442.0 [M+H]+. 1H NMR (400 MHz, MeOH-d4)δ 8.48 (d, J=6.57 Hz, 1H), 7.58 (d, J=8.36 Hz, 1H), 7.55 (s, 1H), 7.33(dd, J=2.02, 8.08 Hz, 1H), 6.41 (d, J=6.06 Hz, 1H), 4.25-4.33 (m, 1H),3.54 (br dd, J=3.79, 11.87 Hz, 1H), 3.34-3.40 (m, 1H), 2.93-3.03 (m,2H), 2.49 (s, 3H), 1.99-2.14 (m, 2H), 1.72-1.91 (m, 2H).

Example 461:(R)-5-(4-Methyl-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-(4-methyl-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a 2-5 mL Biotage microwave vial with a stir bar were added4-methyl-3-(trifluoromethyl)aniline (80 mg, 0.41 mmol),2-chloro-4-iodonicotinonitrile (107 mg, 0.405 mmol), Pd(OAc)₂ (1.8 mg,0.0080 mmol), DPEPhos (6.8 mg, 0.013 mmol), and Cs₂CO₃ (184 mg, 0.565mmol). The vial was sealed, treated with dioxane (0.81 mL), evacuatedand flushed with argon 4×, and stirred at 150° C. under argon for 30min. The reaction was cooled to room temperature and was treated withtert-butyl (3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate(Intermediate 22) (0.49 M in dioxane, 0.83 mL, 0.41 mmol) via syringe.The vial was sealed and evacuated and flushed with argon 4×, and stirredat 150° C. for 15 min. The reaction was then cooled to room temperature,treated with solid CDI (265 mg, 1.63 mmol) in one portion under air,resealed and evacuated and flushed with argon 4×, and stirred at 150° C.for 15 min. The reaction was diluted with EtOAc (10 mL), and washed with0.5 M citric acid and brine (2×8 mL) and 2 M K₂CO₃ (1×5 mL). The organicphase was dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was purified by normal phase flash columnchromatography (SiO2) to give the title compound as a light-beige solid(123 mg, 52.8% yield).

Step B:(R)-5-(4-Methyl-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(4-methyl-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(117.3 mg, 0.204 mmol) in dioxane (1.0 mL) was treated with HCl (3.97 Min dioxane, 2.55 mL, 10.1 mmol) in one portion at room temperature, andthe resulting solution was stirred at room temperature for 1 h. Thereaction was concentrated to dryness to give the title compound as ayellow-beige powder (113.4 mg, 101.7% yield). MS (ESI): mass calcd. forC22H23F3N5O2S, 475.1; m/z found, 476.0 [M+H]+. 1H NMR (400 MHz, MeOH-d4)δ 8.42 (d, J=6.06 Hz, 1H), 7.79 (s, 1H), 7.60-7.68 (m, 2H), 6.29 (d,J=6.06 Hz, 1H), 4.24-4.32 (m, 1H), 3.54 (dd, J=4.04, 12.13 Hz, 1H),3.34-3.40 (m, 1H), 2.92-3.02 (m, 2H), 2.58-2.63 (m, 3H), 2.05-2.14 (m,2H), 1.71-1.91 (m, 2H).

Example 462:4-Oxo-5-(4-phenoxyphenyl)-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 4-fluoronitrobenzene in place of5-fluoro-2-nitrotoluene in step A and using tetrahydrofurfurylamine inplace of tert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate instep G to yield the title compound. MS (ESI): mass calcd. forC26H22N4O4S, 486.5; m/z found, 487.1 [M+H]+. 1H NMR (500 MHz,Chloroform-d) δ 8.28 (d, J=5.4 Hz, 1H), 7.45-7.01 (m, 11H), 6.13 (d,J=5.4 Hz, 1H), 4.10 (dtt, J=10.4, 7.2, 3.0 Hz, 1H), 3.97 (q, J=7.0, 6.1Hz, 1H), 3.81 (q, J=7.4 Hz, 1H), 3.65 (dt, J=14.0, 4.5 Hz, 1H), 3.41(dq, J=17.6, 7.3, 5.7 Hz, 1H), 3.11-3.06 (m, 1H), 2.09-1.87 (m, 3H).

Example 463:N-((3S,4S)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using 4-fluoronitrobenzene in place of5-fluoro-2-nitrotoluene in step A and using tert-buty(3S,4S)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step Gto yield the title compound. MS (ESI): mass calcd. for C28H23N5O5S,541.5; m/z found, 542.2 [M+H]+. 1H NMR (400 MHz, Chloroform-d) 9.57 (s,1H), 8.22-8.12 (m, 1H), 7.47-7.32 (m, 5H), 7.21-7.05 (m, 4H), 6.38-6.25(m, 2H), 6.03-5.92 (m, 1H), 5.71-5.59 (m, 2H), 4.41 (s, 2H), 4.07 (t,J=9.4 Hz, 1H), 3.86 (s, 1H), 3.63-3.51 (m, 3H).

Example 464:N-((3S,4S)-4-Hydroxypyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 4-fluoronitrobenzene in place of5-fluoro-2-nitrotoluene in step A and using tert-butyl(3S,4S)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step Gto yield the title compound. MS (ESI): mass calcd. for C25H21N5O4S,487.5; m/z found, 488.0 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 8.30 (d,J=5.6 Hz, 1H), 7.46-7.37 (m, 4H), 7.22-7.14 (m, 3H), 7.14-7.07 (m, 2H),6.17 (d, J=5.6 Hz, 2H), 6.00 (s, 1H), 4.53 (dt, J=4.2, 2.0 Hz, 1H), 4.39(dddd, J=6.6, 3.1, 2.1, 0.9 Hz, 1H), 3.77 (dd, J=12.6, 6.9 Hz, 2H), 3.56(ddd, J=30.3, 12.5, 3.7 Hz, 2H), 3.35 (s, 1H), 2.00 (s, 1H).

Example 465:(R)-5-(3-Benzylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-butyl3-(5-(3-benzylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a 2-5 mL Biotage microwave vial with a stir bar were added3-benzylaniline (71.8 mg, 0.384 mmol), 2-chloro-4-iodonicotinonitrile(102 mg, 0.384 mmol), Pd(OAc)₂ (1.8 mg, 0.0080 mmol), DPEPhos (6.6 mg,0.012 mmol), and Cs₂CO₃ (173 mg, 0.531 mmol). The vial was sealed,treated with dioxane (0.77 mL), evacuated and flushed with argon 4×, andstirred at 150° C. under argon for 30 min. The reaction was cooled toroom temperature and was treated with tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate22) (0.49 M in dioxane, 0.79 mL, 0.39 mmol) via syringe. The vial wassealed and evacuated and flushed with argon 4×, and stirred at 150° C.for 15 min. The reaction was then cooled to room temperature, treatedwith solid CDI (252 mg, 1.55 mmol) in one portion under air, resealedand evacuated and flushed with argon 4×, and stirred at 150° C. for 15min. The reaction was diluted with EtOAc (10 mL), and washed with 0.5 Mcitric acid and brine (2×8 mL) and 2 M K₂CO₃ (1×5 mL). The organic phasewas dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness.The residue was purified by normal phase flash column chromatography(SiO2) to give the title compound as a light-beige solid (122 mg, 54.5%yield).

Step B:(R)-5-(3-Benzylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(3-benzylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(119.8 mg, 0.205 mmol) in dioxane (1.0 mL) was treated with HCl (3.97 Min dioxane, 2.55 mL, 10.1 mmol) in one portion at room temperature, andthe resulting solution was stirred at room temperature for 1 h. Thereaction was concentrated to dryness to give the title compound as ayellow powder (113.5 mg, 98.03% yield). MS (ESI): mass calcd. forC27H25N5O2S, 483.2; m/z found, 484.2 [M+H]+. 1H NMR (400 MHz, MeOH-d4) δ8.44 (d, J=6.06 Hz, 1H), 7.56 (t, J=7.58 Hz, 1H), 7.45 (d, J=7.58 Hz,1H), 7.16-7.33 (m, 7H), 6.32 (d, J=6.57 Hz, 1H), 4.24-4.33 (m, 1H), 4.08(s, 2H), 3.54 (dd, J=4.04, 12.13 Hz, 1H), 3.33-3.39 (m, 1H), 2.93-3.03(m, 2H), 2.04-2.14 (m, 2H), 1.72-1.91 (m, 2H).

Example 466:(R)-4-Oxo-5-(3-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a 2-5 mL Biotage microwave vial with a stir bar were added3-phenoxyaniline (82.8 mg, 0.447 mmol), 2-chloro-4-iodonicotinonitrile(117 mg, 0.443 mmol), Pd(OAc)₂ (2.1 mg, 0.0094 mmol), DPEPhos (7.3 mg,0.014 mmol), and Cs₂CO₃ (201 mg, 0.617 mmol). The vial was sealed,treated with dioxane (0.89 mL), evacuated and flushed with argon 4×, andstirred at 150° C. under argon for 30 min. The reaction was cooled toroom temperature and was treated with tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate22) (0.49 M in dioxane, 0.91 mL, 0.45 mmol) via syringe. The vial wassealed and evacuated and flushed with argon 4×, and stirred at 150° C.for 15 min. The reaction was then cooled to room temperature, treatedwith solid CDI (252 mg, 1.55 mmol) in one portion under air, resealedand evacuated and flushed with argon 4×, and stirred at 150° C. for 15min. The reaction was diluted with EtOAc (10 mL), and washed with 0.5 Mcitric acid and brine (2×8 mL) and 2 M K₂CO₃ (1×5 mL). The organic phasewas dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness.The residue was purified by normal phase flash column chromatography(SiO₂) to give the title compound as a light-beige solid (168 mg, 64.7%yield).

Step B:(R)-4-Oxo-5-(3-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of ((R)-tert-butyl3-(4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(168 mg, 0.287 mmol) in dioxane (1.4 mL) was treated with HCl (3.97 M indioxane, 3.60 mL, 14.3 mmol) in one portion at room temperature, and theresulting solution was stirred at room temperature for 1 h. The reactionwas concentrated to dryness to give the title compound as a yellowpowder (143.5 mg, 85.71% yield). MS (ESI): mass calcd. for C26H23N5O3S,485.2; m/z found, 486.1 [M+H]+. 1H NMR (400 MHz, MeOH-d4) δ 8.47 (d,J=6.06 Hz, 1H), 7.61 (t, J=8.08 Hz, 1H), 7.39 (t, J=8.08 Hz, 2H),7.07-7.22 (m, 6H), 6.43 (d, J=6.57 Hz, 1H), 4.23-4.32 (m, 1H), 3.49-3.59(m, 1H), 3.34-3.40 (m, 1H), 2.91-3.03 (m, 2H), 2.00-2.12 (m, 2H),1.71-1.91 (m, 2H).

Example 467:N-((3R,5S)-5-Methoxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed onN-((3R,5S)-5-Methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 268, 868 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5m 250×20 mm, Mobile phase: 55% CO₂, 45% MeOH) to give the title compound(as the *S atropisomer; 4 mg, 0.5% yield). MS (ESI): mass calcd. forC₂₈H₂₇N₅O₄S, 529.6; m/z found, 529.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): δ8.34 (d, J=5.5 Hz, 1H), 7.52-7.34 (m, 3H), 7.21-7.06 (m, 4H), 7.05-6.90(m, 2H), 6.00 (d, J=5.5 Hz, 1H), 4.26 (s, 1H), 3.60-3.40 (m, 4H),3.36-3.12 (m, 1H), 2.89 (dd, J=73.7, 13.7 Hz, 2H), 2.21-2.03 (m, 4H),1.92 (d, J=14.6 Hz, 1H), 1.25 (s, 3H).

Example 468:N-((3R,5S)-5-Methoxypiperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed onN-((3R,5S)-5-Methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 268, 868 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5m 250×20 mm, Mobile phase: 55% CO₂, 45% MeOH) to give the title compound(as the *R atropisomer; 4 mg, 0.5% yield). MS (ESI): mass calcd. forC₂₈H₂₇N₅O₄S, 529.6; m/z found, 529.2 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): δ8.35 (d, J=5.6 Hz, 1H), 7.42-7.38 (m, 2H), 7.24-6.90 (m, 8H), 6.00 (s,1H), 4.20-4.08 (m, 1H), 3.53-3.35 (m, 5H), 3.26-3.00 (m, 1H), 2.95-2.71(m, 2H), 2.16-1.86 (m, 6H).

Example 469:(*S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 202, 818 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H 5m 250×20 mm, Mobile phase: 55% CO₂, 45% MeOH) and a and a secondpurification (30 mg from fraction 2, first purification) was performedvia chiral SFC (Stationary phase: CHIRALCEL OJ-H 5 m 250×20 mm, Mobilephase: 70% CO₂, 30% EtOH) to give the title compound (as the *Satropisomer; 10 mg, 1.2% yield). MS (ESI): mass calcd. for C₂₆H₂₁N₅O₄S,499.5; m/z found, 499.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): δ 9.95 (s, 1H),8.35 (d, J=5.4 Hz, 1H), 7.46-7.33 (m, 2H), 7.26-6.85 (m, 7H), 6.57 (s,1H), 6.00 (d, J=5.5 Hz, 1H), 4.93-4.81 (m, 1H), 3.90-3.73 (m, 1H), 3.43(dd, J=10.5, 2.6 Hz, 1H), 2.91-2.78 (m, 1H), 2.57 (dd, J=17.3, 3.2 Hz,1H), 2.14 (s, 3H).

Example 470:(*S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 202, 818 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H 5m 250×20 mm, Mobile phase: 55% CO₂, 45% MeOH) and a and a secondpurification (30 mg from fraction 2, first purification) was performedvia chiral SFC (Stationary phase: CHIRALCEL OJ-H 5 m 250×20 mm, Mobilephase: 70% CO₂, 30% EtOH) to give the title compound (as the *Ratropisomer; 10 mg, 1.2% yield). MS (ESI): mass calcd. for C₂₆H₂₁N₅O₄S,499.5; m/z found, 499.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): δ 10.07 (s,1H), 8.34 (d, J=5.5 Hz, 1H), 7.48-7.31 (m, 2H), 7.24-6.89 (m, 7H), 6.71(s, 1H), 5.99 (d, J=5.3 Hz, 1H), 4.85 (s, 1H), 3.81 (dd, J=10.6, 5.9 Hz,1H), 3.45 (d, J=10.7 Hz, 1H), 2.94-2.68 (m, 1H), 2.60 (d, J=17.2 Hz,1H), 2.13 (s, 3H).

Example 471:(*R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 202, 818 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H 5m 250×20 mm, Mobile phase: 55% CO₂, 45% MeOH) to give the title compound(as the *S atropisomer; 16 mg, 2.0% yield). MS (ESI): mass calcd. forC₂₆H₂₁N₅O₄S, 499.5; m/z found, 499.1 [M+H]⁺. 1H NMR (600 MHz,Chloroform-d) δ 8.34 (d, J=5.5 Hz, 1H), 7.49-7.34 (m, 2H), 7.24-6.85 (m,7H), 6.61-6.46 (m, 1H), 6.01-5.90 (m, 1H), 4.85 (s, 1H), 3.92-3.75 (m,1H), 3.50-3.36 (m, 1H), 2.90-2.76 (m, 1H), 2.56 (d, J=17.2 Hz, 1H), 2.13(s, 3H).

Example 472:(*R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 202, 818 mg) via chiral SFC (Stationary phase: CHIRALCEL OJ-H 5m 250×20 mm, Mobile phase: 55% CO₂, 45% MeOH) to give the title compound(as the *R atropisomer; 17 mg, 2.1% yield). MS (ESI): mass calcd. forC₂₆H₂₁N₅O₄S, 499.5; m/z found, 499.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃): δ10.03 (s, 1H), 8.32 (s, 1H), 7.47-7.29 (m, 3H), 7.21-6.66 (m, 7H), 5.97(s, 1H), 4.84 (s, 1H), 3.93-3.65 (m, 1H), 3.50-3.28 (m, 1H), 2.79 (s,1H), 2.59 (d, J=17.2 Hz, 1H), 2.12 (s, 3H).

Example 473:(R,*E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R,ZE)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared as in Example 116 to yield the titlecompound.

Step B:(R,*E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R,ZE)-N-(1-(but-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(930 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5 μm 250×20mm, Mobile phase: 55% CO₂, 45% MeOH) and a second purification (11 mgfrom fraction 2, first purification) was performed via chiral SFC(Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 40% CO₂,60% MeOH) to give the title compound (as the *E isomer and the *Satropisomer; 2 mg, 0.2% yield). MS (ESI): mass calcd. for C₃₁H₂₉N₅O₄S,567.7; m/z found, 567.2 [M+H]⁺. 1H NMR (600 MHz, Chloroform-d) δ 9.46(s, 1H), 8.43-8.25 (m, 1H), 7.48-7.34 (m, 2H), 7.23-7.13 (m, 2H),7.13-7.06 (m, 2H), 7.01 (s, 1H), 6.96 (dd, J=8.5, 2.8 Hz, 1H), 6.53-5.98(m, 3H), 4.38-3.23 (m, 2H), 2.13 (s, 4H), 1.91 (s, 3H), 1.25 (s, 6H).

Example 474:(R,*E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R,ZE)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared as in Example 116 to yield the titlecompound.

Step B:(R,*E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R,ZE)-N-(1-(but-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(930 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5 μm 250×20mm, Mobile phase: 55% CO₂, 45% MeOH) to give the title compound (as the*E isomer and the *R atropisomer; 7 mg, 0.8% yield). MS (ESI): masscalcd. for C₃₁H₂₉N₅O₄S, 567.7; m/z found, 567.2 [M+H]⁺. ¹H NMR (600 MHz,CDCl₃): δ 5.46 (d, J=7.3 Hz, OH), 4.28-3.12 (m, 5H), 2.21-1.77 (m, 6H),1.25 (s, 3H), 5.45-5.39 (m, OH), 9.48 (s, 1H), 8.36 (dd, J=11.1, 5.5 Hz,1H), 7.48-7.32 (m, 2H), 7.24-6.86 (m, 7H), 6.31-5.95 (m, 3H).

Example 475:(R,*Z)—N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R,ZE)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared as in Example 116 to yield the titlecompound.

Step B:(R,*Z)—N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R,ZE)-N-(1-(but-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(930 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5 m 250×20 mm,Mobile phase: 55% CO₂, 45% MeOH) and a second purification (11 mg fromfraction 2, first purification) was performed via chiral SFC (Stationaryphase: CHIRALPAK AD-H 5 m 250×20 mm, Mobile phase: 40% CO₂, 60% MeOH) togive the title compound (as the *Z isomer and the *R atropisomer; 4 mg,0.4% yield). MS (ESI): mass calcd. for C₃₁H₂₉N₅O₄S, 567.7; m/z found,567.2 [M+H]⁺. 1H NMR (600 MHz, Chloroform-d) δ 9.46 (s, 1H), 8.44-8.31(m, 1H), 7.48-7.37 (m, 2H), 7.23-6.87 (m, 6H), 6.32-5.38 (m, 4H),4.22-3.15 (m, 5H), 2.22-1.55 (m, 8H), 1.44-0.99 (m, 2H).

Example 476:(R,*Z)—N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R,ZE)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared as in Example 116 to yield the titlecompound.

Step B:(R,*Z)—N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R,ZE)-N-(1-(but-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(930 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5 μm 250×20mm, Mobile phase: 55% CO₂, 45% MeOH) to give the title compound (as the*Z isomer and the *S atropisomer; 4 mg, 0.4% yield). MS (ESI): masscalcd. for C₃₁H₂₉N₅O₄S, 567.7; m/z found, 567.2 [M+H]⁺. ¹H NMR (600 MHz,CDCl₃): δ 9.47 (s, 1H), 8.36 (s, 1H), 7.47-7.34 (m, 2H), 7.22-6.84 (m,7H), 6.43-6.23 (m, 1H), 6.10-5.79 (m, 1H), 4.52-3.22 (m, 6H), 2.22-1.65(m, 6H), 1.45-0.93 (m, 4H).

Example 477:(R,*Z)—N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R,EZ)—N-(1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 29; 1089 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5μm 250×20 mm, Mobile phase: 55% CO₂, 45% mixture of MeOH/iPrOH, 50/50,v/v) and a second purification (55 mg from fraction 3, firstpurification) was performed via chiral SFC (Stationary phase: CHIRALCELOJ-H 5 m 250×20 mm, Mobile phase: 75% CO₂, 25% iPrOH) to give the titlecompound (as the *Z isomer and the *S atropisomer; 6 mg, 0.6% yield). MS(ESI): mass calcd. for C₃₆H₃₆N₆O₅S, 664.8; m/z found, 664.3 [M+H]⁺. ¹HNMR (600 MHz, CDCl₃): δ 9.48 (s, 1H), 8.36 (dd, J=5.3, 0.9 Hz, 1H),7.48-7.36 (m, 2H), 7.22-6.92 (m, 6H), 6.56 (d, J=7.7 Hz, 1H), 6.02 (dd,J=5.5, 1.6 Hz, 1H), 5.77-5.54 (m, 1H), 4.28-4.13 (m, 1H), 4.08-3.57 (m,1H), 3.57-3.30 (m, 3H), 2.19-2.10 (m, 3H), 2.11-1.65 (m, 2H), 1.65-1.54(m, 4H), 1.51-1.27 (m, 5H), 1.23-1.19 (m, 1H), 1.16 (dt, J=19.0, 6.9 Hz,3H).

Example 478:(R,*E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R,EZ)—N-(1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 29; 1089 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5μm 250×20 mm, Mobile phase: 55% CO₂, 45% mixture of MeOH/iPrOH, 50/50,v/v) and a second purification (55 mg from fraction 3, firstpurification) was performed via chiral SFC (Stationary phase: CHIRALCELOJ-H 5 μm 250×20 mm, Mobile phase: 75% CO₂, 25% iPrOH) to give the titlecompound (as the *E isomer and the *S atropisomer; 25 mg, 2.3% yield).MS (ESI): mass calcd. for C₃₆H₃₆N₆O₅S, 664.8; m/z found, 664.3 [M+H]⁺.¹H NMR (600 MHz, CDCl₃): δ 9.44 (s, 1H), 8.36 (d, J=5.4 Hz, 1H),7.46-7.34 (m, 2H), 7.23-6.90 (m, 6H), 6.10-5.53 (m, 2H), 4.23-4.07 (m,1H), 4.02-3.78 (m, 1H), 3.69-3.30 (m, 5H), 2.14 (s, 3H), 2.10-1.91 (m,2H), 1.91-1.63 (m, 4H), 1.57-1.39 (m, 4H), 1.28-1.24 (m, 4H).

Example 479:(R,*Z)—N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R,EZ)—N-(1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 29; 1089 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5μm 250×20 mm, Mobile phase: 55% CO₂, 45% mixture of MeOH/iPrOH, 50/50,v/v) and a second purification (56 mg from fraction 2, firstpurification) was performed via chiral SFC (Stationary phase: CHIRALCELOJ-H 5 μm 250×20 mm, Mobile phase: 75% CO₂, 25% iPrOH) to give the titlecompound (as the *Z isomer and the *R atropisomer; 6 mg, 0.6% yield). MS(ESI): mass calcd. for C₃₆H₃₆N₆O₅S, 664.8; m/z found, 664.3 [M+H]⁺. ¹HNMR (600 MHz, CDCl₃): δ 9.49 (s, 1H), 8.36 (d, J=5.5 Hz, 1H), 7.50-7.38(m, 2H), 7.23-6.91 (m, 6H), 6.60-6.47 (m, 1H), 6.02 (d, J=5.5 Hz, 1H),5.79-5.53 (m, 1H), 4.32-3.30 (m, 5H), 2.21-1.54 (m, 10H), 1.42-1.34 (m,5H), 1.21-1.07 (m, 3H).

Example 480:(R,*E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

A chiral purification was performed on(R,EZ)—N-(1-(2-cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 29; 1089 mg) via chiral SFC (Stationary phase: CHIRALCEL OD-H 5μm 250×20 mm, Mobile phase: 55% CO₂, 45% mixture of MeOH/iPrOH, 50/50,v/v) and a second purification (56 mg from fraction 2, firstpurification) was performed via chiral SFC (Stationary phase: CHIRALCELOJ-H 5 μm 250×20 mm, Mobile phase: 75% CO₂, 25% iPrOH) to give the titlecompound (as the *E isomer and the *R atropisomer; 26 mg, 2.4% yield).MS (ESI): mass calcd. for C₃₆H₃₆N₆O₅S, 664.8; m/z found, 664.3 [M+H]⁺.¹H NMR (600 MHz, CDCl₃): δ 9.44 (s, 1H), 8.37 (d, J=5.5 Hz, 1H),7.46-7.35 (m, 2H), 7.24-6.87 (m, 7H), 6.03 (d, J=5.5 Hz, 2H), 4.39-3.08(m, 5H), 2.23-1.57 (m, 8H), 1.55-1.05 (m, 10H).

Example 481:N-((3R,5R)-1-Acryl-5-methoxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsG-I in Example 1, and using5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 16) and tert-butyl(3R,5R)-3-amino-5-methoxypiperidine-1-carboxylate (Intermediate 6) inplace of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₁H₂₉N₅O₅S, 583.7; m/z found, 584.5[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.29 (d, J=5.5 Hz, 1H), 7.42-7.35 (m,2H), 7.34-7.29 (m, 1H), 7.19-7.12 (m, 1H), 7.11-6.91 (m, 4H), 6.85-6.69(m, 1H), 6.22-6.13 (m, 1H), 6.03 (d, J=5.6 Hz, 1H), 5.76-5.65 (m, 1H),4.70-4.50 (m, 1H), 4.32-4.07 (m, 2H), 3.72-3.56 (m, 1H), 3.38-3.33 (m,3H), 3.26-2.65 (m, 2H), 2.28-2.12 (m, 1H), 2.10 (s, 3H), 1.97-1.69 (m,1H).

Example 482:N-((3R,5S)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsG-I in Example 1, and using5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 16) and tert-butyl(3R,5S)-3-amino-5-methoxypiperidine-1-carboxylate (Intermediate 29) inplace of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₁H₂₉N₅O₅S, 583.7; m/z found, 584.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.39-8.29 (m, 1H), 7.47-7.36 (m, 2H),7.30-7.27 (m, 1H), 7.20-7.15 (m, 1H), 7.12-7.03 (m, 3H), 7.02-6.93 (m,1H), 6.85-6.60 (m, 1H), 6.17-6.05 (m, 2H), 5.79-5.60 (m, 1H), 4.44-4.26(m, 1H), 4.23-4.12 (m, 1H), 4.03-3.92 (m, 1H), 3.68-3.55 (m, 2H),3.53-3.45 (m, 3H), 3.44-3.35 (m, 1H), 2.17-2.09 (m, 4H), 2.02-1.96 (m,1H).

Example 483:N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsG-I in Example 1, and using5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 16) and tert-butyl(3R,5R)-3-amino-5-hydroxypiperidine-1-carboxylate (Intermediate 4) inplace of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₅S, 569.6; m/z found, 570.5[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30 (d, J=5.5 Hz, 1H), 7.46-7.36 (m,2H), 7.32-7.26 (m, 1H), 7.21-7.13 (m, 1H), 7.12-7.03 (m, 3H), 7.00-6.92(m, 1H), 6.85-6.68 (m, 1H), 6.26-6.12 (m, 1H), 6.05 (d, J=5.6 Hz, 1H),5.78-5.66 (m, 1H), 4.59-4.54 (m, 1H), 4.44-4.32 (m, 1H), 4.16-4.02 (m,2H), 3.96-3.87 (m, 0.5H), 3.38-3.33 (m, 1H), 2.95-2.83 (m, 0.5H), 2.11(s, 3H), 2.07-1.84 (m, 2H).

Example 484:N-((3R,5S)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(*S)-(2-methphenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsG-I in Example 1, and using5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 16) and tert-butyl(3R,5S)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 3) inplace of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₀H₂₆FN₅O₄S, 571.6; m/z found, 572.4[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30 (d, J=5.5 Hz, 1H), 7.43-7.35 (m,2H), 7.30 (d, J=8.6 Hz, 1H), 7.19-7.11 (m, 1H), 7.10-7.01 (m, 3H),6.87-6.63 (m, 1H), 6.88-6.63 (m, 1H), 6.27-6.14 (m, 1H), 6.04 (d, J=5.5Hz, 1H), 5.81-5.66 (m, 1H), 5.08-4.85 (m, 1H), 4.75-4.63 (m, 1H),4.35-4.16 (m, 2H), 3.15-2.64 (m, 2H), 2.43-2.21 (m, 1H), 2.10 (s, 3H),2.04-1.76 (m, 1H).

Example 485:N-(4-Cyano-1,4-oxazepan-6-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:5-(*)-(2-Methyl-4-phenoxyphenyl)-N-(1,4-oxazepan-6-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H (including Chiral Resolution Method A after step F to obtain the *Satropisomer) in Example 1, and using tert-butyl6-amino-1,4-oxazepane-4-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G, to yieldthe title compound (148 mg).

Step B:N-(4-Cyano-1,4-oxazepan-6-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a mixture of5-(S)-(2-methyl-4-phenoxyphenyl)-N-(1,4-oxazepan-6-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(123 mg, 0.239 mmol), triethylamine (49 mg, 0.48 mmol) in DCM (5 mL) wasadded BrCN (31 mg, 0.29 mmol) and was stirred at room temperature for 30minutes. The mixture was concentrated to dryness and purified by flashcolumn chromatography, and then by preparative TLC to yield the titlecompound (101 mg, 99.3% yield). MS (ESI): mass calcd. for C₂₈H₂₄N₆O₄S,540.6; m/z found, 541.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.22 (s,1H), 8.34-8.29 (m, 1H), 8.17-8.10 (m, 1H), 7.45-7.39 (m, 2H), 7.37-7.33(m, 1H), 7.20-7.15 (m, 1H), 7.12-7.08 (m, 2H), 7.08-7.05 (m, 1H),6.97-6.94 (m, 1H), 5.98-5.94 (m, 1H), 4.35-4.25 (m, 1H), 3.90-3.82 (m,1H), 3.81-3.65 (m, 3H), 3.57-3.50 (m, 1H), 3.40-3.32 (m, 3H), 2.04 (s,3H).

Example 486:N-((3S,4S)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral Resolution Method A after step F to obtain the *Satropisomer) in Example 1, and using tert-butyl(3S,4S)-3-amino-4-fluoro-pyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G,to yield the title compound. MS (ESI): mass calcd. for C₂₉H₂₄FN₅O₄S,557.6; m/z found, 558.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d,J=5.6 Hz, 1H), 7.45-7.35 (m, 2H), 7.34-7.26 (m, 1H), 7.22-7.13 (m, 1H),7.13-7.02 (m, 3H), 7.00-6.93 (m, 1H), 6.71-6.55 (m, 1H), 6.35-6.28 (m,1H), 6.06 (d, J=5.6 Hz, 1H), 5.81-5.75 (m, 1H), 5.36-5.15 (m, 1H),4.76-4.64 (m, 1H), 4.09-3.75 (m, 4H), 2.13-2.09 (m, 3H).

Example 487:(R,E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98, 300 mg, 0.601 mmol), 2-cyanoacetic acid (102 mg, 1.20mmol), HATU (297 mg, 0.780 mmol), and diisopropylethylamine (155 mg,1.20 mmol) in DMF (5 mL) was stirred at rt for 1 h. The mixture waspurified by flash column chromatography to yield the title compound aswhite solid (225 mg, 66.2% yield).

Step B:(R,E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(1-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(70 mg, 0.12 mmol), 2-ethoxy-2-methyl-propanal (43 mg, 0.37 mmol),piperidine (0.3 mL), and ethanol (10 mL) was added to a flask andstirred at rt for 3 h. The mixture was concentrated to dryness andpurified by flash column chromatography to yield the title compound aswhite solid (77 mg, 92% yield). MS (ESI): mass calcd. for C₃₆H₃₆N₆O₅S,664.8; m/z found, 665.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33-8.26 (m,1H), 7.42-7.35 (m, 2H), 7.35-7.28 (m, 1H), 7.19-7.12 (m, 1H), 7.10-7.01(m, 3H), 7.01-6.93 (m, 1H), 6.91-6.83 (m, 1H), 6.07-6.01 (m, 1H),4.48-3.81 (m, 3H), 3.59-3.34 (m, 3H), 3.24-2.86 (m, 1H), 2.15-1.99 (m,4H), 1.96-1.84 (m, 1H), 1.83-1.58 (m, 2H), 1.50-1.32 (m, 6H), 1.25-1.11(m, 3H).

Example 488:(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98, 90 mg, 0.18 mmol), (E)-4-(dimethylamino)but-2-enoic acid(46 mg, 0.36 mmol), HATU (89 mg, 0.23 mmol), and diisopropylethylamine(46 mg, 0.36 mmol) in DMF (5 mL) was stirred at rt for 1 h. The mixturewas purified by flash column chromatography to yield the title compoundas white solid (75 mg, 63% yield). MS (ESI): mass calcd. forC₃₃H₃₄N₆O₄S, 610.7; m/z found, 611.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.44 (s, 1H), 8.34-8.28 (m, 1H), 7.43-7.34 (m, 2H), 7.34-7.27 (m, 1H),7.20-7.11 (m, 1H), 7.11-7.01 (m, 3H), 7.01-6.91 (m, 1H), 6.89-6.79 (m,1H), 6.76-6.62 (m, 1H), 6.10-6.01 (m, 1H), 4.38-3.85 (m, 3H), 3.77-3.63(m, 2H), 3.24-3.10 (m, 1H), 2.99-2.83 (m, 1H), 2.76-2.63 (m, 6H),2.16-2.00 (m, 4H), 1.92-1.81 (m, 1H), 1.81-1.65 (m, 1H), 1.65-1.48 (m,1H).

Example 489:N-((3S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral Resolution Method A after step F to obtain the *Satropisomer) in Example 1, and using tert-butyl(3S,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate (Intermediate 24) inplace of tert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate instep G, to yield the title compound. MS (ESI): mass calcd. forC₂₉H₂₅N₅O₅S, 555.6; m/z found, 556.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.29 (d, J=5.6 Hz, 1H), 7.43-7.36 (m, 2H), 7.34-7.27 (m, 1H), 7.19-7.13(m, 1H), 7.11-7.03 (m, 3H), 7.01-6.93 (m, 1H), 6.67-6.50 (m, 1H),6.32-6.22 (m, 1H), 6.04 (d, J=5.5 Hz, 1H), 5.79-5.69 (m, 1H), 4.66-4.39(m, 2H), 4.07-3.50 (m, 4H), 2.10 (s, 3H).

Example 490:N-((3S,4S)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral Resolution Method A after step F to obtain the *Satropisomer) in Example 1, and using tert-butyl(3S,4S)-3-amino-4-methoxy-pyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G,to yield the title compound. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₅S,569.6; m/z found, 570.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.38 (d,J=5.5 Hz, 1H), 7.53-7.42 (m, 2H), 7.39-7.31 (m, 1H), 7.26-7.20 (m, 1H),7.17-7.08 (m, 3H), 7.08-6.98 (m, 1H), 6.76-6.57 (m, 1H), 6.39-6.28 (m,1H), 6.12 (d, J=5.5 Hz, 1H), 5.86-5.76 (m, 1H), 4.69-4.62 (m, 1H),4.13-3.93 (m, 2H), 3.92-3.66 (m, 3H), 3.57-3.50 (m, 3H), 2.17 (s, 3H).

Example 491:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)pyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 36, 80 mg, 0.15 mmol) in DMF (3 mL) were added(E)-2-Cyano-3-cyclopropyl-prop-2-enoic acid (Intermediate 17) (32 mg,0.23 mmol), HATU (70 mg, 0.18 mmol), and triethylamine (0.085 mL, 0.61mmol). The reaction mixture was stirred at rt overnight, then purifiedusing flash column chromatography to yield the title compound as ayellow solid (40 mg, 43% yield). MS (ESI): mass calcd. for C₃₃H₂₈N₆O₄S,604.7; m/z found, 605.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ8.27 (d, J=5.5 Hz, 1H), 7.42-7.32 (m, 2H), 7.30-7.21 (m, 1H), 7.17-7.07(m, 1H), 7.07-7.01 (m, 2H), 7.01-6.99 (m, 1H), 6.94-6.88 (m, 1H),6.74-6.65 (m, 1H), 5.97 (d, J=5.5 Hz, 1H), 4.58-4.47 (m, 1H), 4.09-3.99(m, 1H), 3.95-3.77 (m, 1H), 3.75-3.67 (m, 1H), 3.64-3.56 (m, 1H),3.52-3.41 (m, 1H), 2.22-2.12 (m, 1H), 2.04 (s, 3H), 1.96-1.88 (m, 1H),1.20-1.14 (m, 2H), 0.90-0.83 (m, 2H).

Example 492:(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R,E)-tert-Butylmethyl(4-(3-(5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidin-1-yl)-4-oxobut-2-en-1-yl)carbamate

A solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 36, 90 mg, 0.19 mmol),(E)-4-[tert-butoxycarbonyl(methyl)amino]but-2-enoic acid (Intermediate10, 80 mg, 0.37 mmol), HATU (91 mg, 0.24 mmol), anddiisopropylethylamine (72 mg, 0.56 mmol) in DMF (5 mL) was stirred at rtfor 1 h. The reaction mixture was purified by flash columnchromatography to yield the title compound as white solid (98 mg, 79%yield).

Step B:(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The reagents (R,E)-tert-butylmethyl(4-(3-(5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidin-1-yl)-4-oxobut-2-en-1-yl)carbamate(98 mg, 0.14 mmol), concentrated HCl (5 mL), and MeOH (5 mL) were addedto a flask and stirred at rt for 1 h. The mixture was concentrated todryness and the residue was purified by flash column chromatography toyield the title compound as white solid (64 mg, 71% yield). MS (ESI):mass calcd. for C₃₁H₃₀N₆O₄S, 582.7; m/z found, 583.4 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.47 (s, 1H), 8.36-8.30 (m, 1H), 7.44-7.36 (m, 2H),7.32-7.26 (m, 1H), 7.20-7.13 (m, 1H), 7.12-7.03 (m, 3H), 7.01-6.94 (m,1H), 6.81-6.60 (m, 2H), 6.10-6.05 (m, 1H), 4.15-3.46 (m, 7H), 2.72-2.65(m, 3H), 2.40-2.21 (m, 1H), 2.21-2.04 (m, 4H).

Example 493:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G (including Chiral Resolution Method A after step F to obtain the *Satropisomer) in Example 1, and using (3R)-1-methylpyrrolidin-3-amine inplace of tert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate instep G, to yield the title compound. MS (ESI): mass calcd. forC₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.49 (s, 1H), 8.32 (d, J=5.5 Hz, 1H), 7.46-7.36 (m, 2H), 7.32-7.26 (m,1H), 7.20-7.14 (m, 1H), 7.13-7.03 (m, 3H), 7.00-6.94 (m, 1H), 6.07 (d,J=5.6 Hz, 1H), 4.66-4.53 (m, 1H), 3.68-3.55 (m, 1H), 3.52-3.42 (m, 2H),3.26-3.15 (m, 1H), 2.89 (s, 3H), 2.6-2.46 (m, 1H), 2.29-2.17 (m, 1H),2.10 (s, 3H).

Example 494:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*S)(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 36, 100 mg, 0.19 mmol), 3-(methylsulfonyl)propanoic acid(29 mg, 0.19 mmol), HATU (146 mg, 0.384 mmol), and triethylamine (97 mg,0.96 mmol) in DMF 3 mL) was stirred at rt for 2 h, then purified byflash column chromatography to yield the title compound as a white solid(62 mg, 99% yield). MS (ESI): mass calcd. for C₃₀H₂₉N₅O₆S₂, 619.7; m/zfound, 620.3 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H),8.34-8.29 (m, 1H), 7.46-7.39 (m, 2H), 7.36 (d, J=8.6 Hz, 1H), 7.22-7.15(m, 1H), 7.13-7.04 (m, 3H), 6.99-6.93 (m, 1H), 5.98-5.91 (m, 1H),4.55-4.35 (m, 1H), 3.85-3.30 (m, 6H), 2.98 (s, 3H), 2.78-2.65 (m, 2H),2.24-2.06 (m, 1H), 2.04 (s, 3H), 2.03-1.89 (m, 1H).

Example 495:(R)—N-(1-(2-Methoxyacetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98, 80 mg, 0.15 mmol) in DMF (2 mL) were added 2-methoxyaceticacid (20 mg, 0.22 mmol), HATU (68 mg, 0.18 mmol), triethylamine (0.083mL, 0.60 mmol). The reaction mixture was stirred at rt for 3 h. Thereaction mixture was purified by flash column chromatography to yieldthe title compound as a yellow solid (67 mg, 98% yield). MS (ESI): masscalcd. for C₃₀H₂₉N₅O₅S, 571.6; m/z found, 572.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.35-8.27 (m, 1H), 7.43-7.33 (m, 2H), 7.31-7.24 (m, 1H),7.20-7.15 (m, 1H), 7.12-7.02 (m, 3H), 7.01-6.94 (m, 1H), 6.05 (d, J=5.4Hz, 1H), 4.54 (s, 2H), 4.24-4.15 (m, 2H), 3.98-3.88 (m, 1H), 3.40 (s,3H), 3.15-3.04 (m, 1H), 2.98-2.84 (m, 1H), 2.12 (s, 3H), 2.06-1.99 (m,1H), 1.89-1.80 (m, 1H), 1.78-1.53 (m, 2H).

Example 496:N-(1-Acryloylazetidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral Resolution Method A after step F to obtain the *Satropisomer) in Example 1, and using tert-butyl3-aminoazetidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G, to yieldthe title compound. MS (ESI): mass calcd. for C₂₈H₂₃N₅O₄S, 525.6; m/zfound, 526.7 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.32 (s, 1H), 8.82(s, 1H), 8.51-8.22 (m, 1H), 7.52-7.42 (m, 2H), 7.41-7.33 (m, 1H),7.27-7.19 (m, 1H), 7.18-7.07 (m, 3H), 7.05-6.95 (m, 1H), 6.43-6.28 (m,1H), 6.22-6.07 (m, 1H), 6.02-5.90 (m, 1H), 5.74-5.64 (m, 1H), 4.84-4.69(m, 1H), 4.62-4.49 (m, 1H), 4.35-4.15 (m, 2H), 4.08-3.91 (m, 1H),2.14-2.04 (m, 3H).

Example 497:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-methyl-5-phenoxypyridin-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, using(R)-5-(3-Methyl-5-phenoxypyridin-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 595) in place ofN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,to yield the title compound. MS (ESI): mass calcd. for C₂₉H₂₆N₆O₄S,554.6; m/z found, 555.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.37-8.33 (d,J=5.5 Hz, 1H), 8.24-8.18 (d, J=2.8 Hz, 1H), 7.55-7.50 (d, J=2.8 Hz, 1H),7.49-7.43 (m, 2H), 7.29-7.23 (m, 1H), 7.21-7.15 (m, 2H), 6.85-6.75 (m,1H), 6.25-6.17 (m, 1H), 6.12-6.08 (d, J=5.5 Hz, 1H), 5.79-5.70 (m, 1H),4.59-4.25 (m, 1H), 4.23-3.92 (m, 2H), 3.26-3.12 (m, 1H), 3.01-2.82 (m,1H), 2.26-2.18 (s, 3H), 2.13-2.04 (m, 1H), 1.93-1.83 (m, 1H), 1.80-1.68(m, 1H), 1.66-1.51 (m, 1H).

Example 498:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′,3′-difluoro-[1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared in a manner analogous to Method 1, stepsC-F in Example 1, and using 3-bromoaniline in place of2-methyl-4-phenoxy-aniline in step C, to yield the title compound.

Step B: (R)-tert-Butyl3-(5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a stirred suspension of5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (3.5 g, 9.0 mmol) in DMF (15 mL) were added tert-butyl(3R)-3-aminopiperidine-1-carboxylate (3.6 g, 18 mmol), HATU (5.1 g, 13mmol), and diisopropylethylamine (2.3 g, 18 mmol). The resulting mixturewas stirred at room temperature overnight. The solvent was removed andthe residue was partitioned between ethyl acetate and water. The organiclayer was separated, shaken with brine and dried over anhydrous Na₂SO₄.The residue was purified by flash column chromatography to yield thetitle compound as yellow solid (3.0 g, 58% yield).

Step C: (R)-tert-Butyl3-(5-(2′,3′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

A mixture of (R)-tert-butyl3-(5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(180 mg, 0.314 mmol), (2,3-difluorophenyl)boronic acid (75 mg, 0.48mmol), Pd(dppf)Cl₂.CH₂Cl₂ (25 mg, 0.031 mmol), and Na₂CO₃ (85 mg, 0.80mmol) in dioxane (7 mL) and H₂O (1 mL) was sparged with N₂ and stirredat 120° C. for 4 h. The reaction was cooled and the mixture was purifiedby flash column chromatography to yield the title compound as yellowsolid (150 mg, 79% yield).

Step D:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′,3′-difluoro-[1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI, in Example 1, using(R)-5-(2′,3′-Difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 706) in place ofN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamideto yield the title compound (54 mg, 44% yield). MS (ESI): mass calcd.for C₂₉H₂₃F₂N₅O₃S, 559.6; m/z found, 560.4 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 10.14 (s, 1H), 8.30 (d, J=5.4 Hz, 1H), 8.15-7.94 (m, 1H),7.81-7.64 (m, 3H), 7.57-7.22 (m, 4H), 6.89-6.63 (m, 1H), 6.15-5.95 (m,2H), 5.69-5.56 (m, 1H), 4.55-4.11 (m, 1H), 4.09-3.88 (m, 1H), 3.84-3.65(m, 1H), 3.15-2.92 (m, 1H), 2.82-2.57 (m, 1H), 2.02-1.87 (m, 1H),1.82-1.53 (m, 2H), 1.49-1.29 (m, 1H).

Example 499:N-((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsG-I in Example 1, and using5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 16) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) in step G. MS (ESI): mass calcd. forC₃₀H₂₆FN₅O₄S, 571.6; m/z found, 572.2 [M+H]⁺. ¹H NMR (400 MHz, CD3OD andDMSO-d₆=2:1): δ 8.42-8.37 (m, 1H), 7.54-7.44 (m, 2H), 7.42-7.35 (m, 1H),7.28-7.22 (m, 1H), 7.21-7.12 (m, 3H), 7.06-6.99 (m, 1H), 6.92-6.71 (m,1H), 6.31-6.17 (m, 1H), 6.13-6.07 (m, 1H), 5.87-5.72 (m, 1H), 4.98-4.62(m, 1H), 4.27-4.10 (m, 2H), 4.04-3.97 (m, 1H), 3.81-3.49 (m, 2H),2.51-2.35 (m, 1H), 2.17 (s, 3H), 2.14-2.02 (m, 1H).

Example 500:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3′-fluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example498, steps A-E, and using (3-fluorophenyl)boronic acid in place of(2,3-difluorophenyl)boronic acid in step C, to yield the title compound.MS (ESI): mass calcd. for C₂₉H₂₄FN₅O₃S, 541.6; m/z found, 542.5 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.15 (s, 1H), 8.29 (d, J=5.5 Hz, 1H),8.13-7.98 (m, 1H), 7.93-7.81 (m, 2H), 7.73-7.62 (m, 1H), 7.61-7.38 (m,4H), 7.25-7.14 (m, 1H), 6.86-6.64 (m, 1H), 6.16-5.98 (m, 2H), 5.69-5.60(m, 1H), 4.58-4.11 (m, 1H), 4.07-3.89 (m, 1H), 3.84-3.70 (m, 1H),3.16-2.89 (m, 1H), 2.83-2.57 (m, 1H), 2.01-1.87 (m, 1H), 1.81-1.56 (m,2H), 1.48-1.31 (m, 1H).

Example 501:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-cyclobutoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using a method analogous to Method 1,Step I in Example 1, using(R)-5-(4-cyclobutoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 605) instead ofN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,followed by subjection to Chiral Resolution Method A to obtain the S*atropisomer. MS (ESI): mass calcd. for C₂₈H₂₉N₅O₄S, 531.6; m/z found,532.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD, 1.3:1 mixture of rotamers): δ 8.30(d, J=5.56 Hz, 1H), 7.20 (d, J=8.59 Hz, 1H), 6.91 (d, J=2.53 Hz, 1H),6.75-6.87 (m, 2H), 6.20 (d, J=16.67 Hz, 1H), 6.02 (d, J=5.56 Hz, 1H),5.71-5.79 (m, 1H), 4.75 (quin, J=7.07 Hz, 1H), 4.48-4.58 (m, 0.5H),4.26-4.35 (m, 0.5H), 4.14-4.22 (m, 0.5H), 3.88-4.07 (m, 1.5H), 3.10-3.23(m, 1H), 2.82-2.98 (m, 1H), 2.44-2.56 (m, 2H), 2.01-2.22 (m, 6H),1.82-1.94 (m, 2H), 1.66-1.82 (m, 2H), 1.50-1.66 (m, 1H).

Example 502:(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared by treating a solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 36) (80 mg, 0.15 mmol) in DMF (3 mL) with(E)-4-(dimethylamino)but-2-enoic acid (30 mg, 0.23 mmol), HATU (70 mg,0.18 mmol), and triethylamine (0.085 mL, 0.61 mmol). The reactionmixture was stirred at rt overnight, then purified by flash columnchromatography to yield the title compound as a yellow solid (77 mg, 95%yield). MS (ESI): mass calcd. for C₃₂H₃₂N₆O₄S, 596.7; m/z found, 597.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.29-8.36 (m, 1H), 7.44-7.35 (m, 2H),7.31-7.25 (m, 1H), 7.20-7.13 (m, 1H), 7.11-7.03 (m, 3H), 7.00-6.94 (m,1H), 6.85-6.75 (m, 1H), 6.60-6.49 (m, 1H), 6.10-6.04 (m, 1H), 4.69-4.57(m, 1H), 4.02-3.81 (m, 1H), 3.77-3.67 (m, 1H), 3.65-3.46 (m, 2H),3.44-3.37 (m, 2H), 2.46 (s, 6H), 2.37-2.23 (m, 1H), 2.18-2.06 (m, 4H).

Example 503:(R,E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98) (85 mg, 0.17 mmol), (E)-4-hydroxybut-2-enoic acid(Intermediate 13) (35 mg, 0.34 mmol), HATU (84 mg, 0.22 mmol), anddiisopropylethylamine (66 mg, 0.51 mmol) in DMF (5 mL) was stirred at rtfor 1 h. Then the mixture was purified by flash column chromatography toyield the title compound as white solid (56 mg, 56% yield). MS (ESI):mass calcd. for C₃₁H₂₉N₅O₅S, 583.7; m/z found, 584.4 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.34-8.29 (m, 1H), 7.43-7.35 (m, 2H), 7.32-7.26 (m, 1H),7.19-7.12 (m, 1H), 7.11-7.02 (m, 3H), 6.99-6.93 (m, 1H), 6.90-6.78 (m,1H), 6.69-6.61 (m, 1H), 6.08-6.03 (m, 1H), 4.35-3.83 (m, 5H), 3.27-3.09(m, 1H), 3.02-2.85 (m, 1H), 2.16-1.98 (m, 4H), 1.91-1.80 (m, 1H),1.80-1.66 (m, 1H), 1.66-1.49 (m, 1H).

Example 504:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

A mixture of compound5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 57) (1.5 g, 3.8 mmol), tert-butyl(3R)-3-aminopiperidine-1-carboxylate (0.77 g, 3.8 mmol), triethylamine(0.78 g, 7.7 mmol), and HATU (1.5 g, 3.8 mmol) in DMF (5 mL) was stirredat rt for 3 h. Water was added and the precipitate was filtered off toyield the title compound as a pale yellow solid (1.6 g, 73% yield).

Step B:(R)-5-(2′-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A mixture of (R)-tert-butyl3-(5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(400 mg, 0.70 mmol), o-tolylboronic acid (105 mg, 0.770 mmol),Pd(dppf)Cl₂ (29 mg, 0.035 mmol), and Na₂CO₃ (148 mg, 1.40 mmol) indioxane (10 mL) and H₂O (1.0 mL) was stirred at 110° C. for 2 h. Thereaction was concentrated to dryness and the residue was purified flashcolumn chromatography. The solid was dissolved in MeOH (4 mL) and HCl (4mL), and the resulting mixture was heated to 50° C. and stirred for 30min. The reaction was concentrated to dryness and the residue waspurified by flash column chromatography to yield the title compound (320mg, 95% yield).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, to yield 80 mg, 48% yield. MS (ESI): mass calcd. forC₃₀H₂₇N₅O₃S, 537.6; m/z found, 538.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.27 (d, J=5.6 Hz, 1H), 7.68-7.60 (m, 1H), 7.51-7.38 (m, 3H), 7.27-7.18(m, 4H), 6.782-6.70 (m, 1H), 6.24-6.11 (m, 2H), 5.76-5.61 (m, 1H),4.55-4.25 (m, 1H), 4.22-3.96 (m, 1H), 3.96-3.88 (m, 1H), 3.19-3.06 (m,1H), 2.90-2.78 (m, 1H), 2.27 (s, 3H), 2.07-1.99 (m, 1H), 1.87-1.79 (m,1H), 1.74-1.62 (m, 1H), 1.59-1.47 (m, 1H).

Example 505:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:2-Chloro-4-((2-methyl-4-(trifluoromethoxy)phenyl)amino)nicotinonitrile

A 10-20 mL microwave vial was charged sequentially with2-chloro-4-iodonicotinonitrile (300.1 mg, 1.135 mmol),2-methyl-4-(trifluoromethoxy)aniline (216.9 mg, 1.135 mmol), Pd(OAc)₂(5.1 mg, 0.023 mmol), bis(2-diphenylphosphinophenyl)ether (18.3 mg,0.0340 mmol), and Cs₂CO₃ (518 mg, 1.59 mmol). The vial was sealed andwas evacuated and refilled with argon three times, and then dioxane (2.2mL) was added. The vial was evacuated and refilled with argon once. Thesuspension was heated for 5 minutes in an oil bath at 50° C. under anargon inlet needle, then the inlet needle was removed and the sealedvial was heated for 30 minutes in an oil bath at 150° C. The crudeproduct was used directly in the next reaction.

Step B: tert-Butyl(3R)-3-[2-sulfanylacetyl)amino]piperidine-1-carboxylate. A 10-20 mLmicrowave vial was charged with (R)-1-Boc-3-aminopiperidine (5.02 g,25.0 mmol)

The vial was sealed and evacuated and back-filled with argon threetimes. Methyl 2-mercaptoacetate (6.72 mL, 75.1 mmol) was added viasyringe in one portion and the vial was heated in an oil bath at 150° C.After 1 h 35 minutes, the mixture was cooled to rt and was purified byflash column chromatography to yield the title compound (5.54 g, 80.6%yield).

Step C: (R)-tert-Butyl3-(3-amino-4-((2-methyl-4-(trifluoromethoxy)phenyl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate

To a sealed tube containing2-chloro-4-((2-methyl-4-(trifluoromethoxy)phenyl)amino)nicotinonitrile(372 mg, 1.14 mmol) was added a 0.5 M solution of tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate in dioxane. Thesuspension was heated in the sealed tube in an oil bath at 150° C. for15 minutes. The mixture was cooled to room temperature and the reactionmixture was used directly in the next reaction.

Step D: (R)-tert-Butyl3-(5-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To (R)-tert-butyl3-(3-amino-4-((2-methyl-4-(trifluoromethoxy)phenyl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylatein dioxane was added CDI (0.745 g, 4.60 mmol). The reaction tube wassealed and the vessel was evacuated and refilled with argon twice. Themixture was heated for 5 minutes in an oil bath at 50° C. under an argoninlet needle, then the argon inlet needle was removed and the mixturewas heated at 150° C. for 10 minutes. The mixture was cooled to roomtemperature. The aqueous phase was extracted with EtOAc (2×50 mL) andthe combined organic extracts were washed with 1 M aqueous HCl (50 mL),followed by saturated aqueous NaCl (50 mL). The organic phase was driedover anhydrous Na₂SO₄, filtered, and concentrated to dryness. Theresidue was purified by flash column chromatography to yield the titlecompound as a tan solid (452.4 mg, 67.37% yield).

Step E:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Method 1,Step I, in Example 1, and using(R)-5-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 413) in place ofN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.The resulting product was purified using chiral SFC (Stationary phase:Whelk 01 (S,S) 5 μm 250×21.1 mm, Mobile phase: 60% CO₂, 40% MeOH) togive the *S atropisomer. MS (ESI): mass calcd. for C₂₅H₂₂F₃N₅O₄S, 545.5;m/z found, 545.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.34 (br. s.,1H), 8.33 (d, J=5.05 Hz, 1H), 8.06-8.24 (m, 1H), 7.51-7.61 (m, 2H), 7.44(d, J=8.08 Hz, 1H), 6.70-6.89 (m, 1H), 6.11 (d, J=17.18 Hz, 1H), 5.92(d, J=5.05 Hz, 1H), 5.69 (d, J=9.60 Hz, 1H), 4.42-4.55 (m, 0.5H),4.17-4.28 (m, 0.5H), 3.94-4.12 (m, 1H), 3.71-3.86 (m, 1H), 2.92-3.14 (m,1H), 2.60-2.82 (m, 1H), 2.15 (s, 3H), 1.89-2.02 (m, 1H), 1.56-1.85 (m,2H), 1.33-1.53 (m, 1H).

Example 506:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(4-oxo-5-(6-phenoxypyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a 2-5 mL Biotage microwave vial containing a stir bar were added6-phenoxypyridin-3-amine (182 mg, 0.0.980 mmol),2-chloro-4-iodonicotinonitrile (256 mg, 0.971 mmol), Pd(OAc)₂ (4.7 mg,0.021 mmol), DPEPhos (15.6 mg, 0.029 mmol), and Cs₂CO₃ (446 mg, 1.37mmol). The vial was sealed, treated with dioxane (1.95 mL), evacuatedand flushed with argon 4×, and stirred at 150° C. under argon for 30min. The reaction was cooled to rt, treated with tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate22) (2.0 mL, 0.49 M, 0.98 mmol) via syringe, evacuated and flushed withargon 4×, and stirred at 150° C. for 15 min. The reaction was cooled tort, treated with solid CDI (628 mg, 3.87 mmol) in one portion, resealed,and evacuated and flushed with argon 4×, and stirred at 150° C. for 15min. The reaction was then diluted with EtOAc (10 mL), and washed with0.5 M citric acid/brine solution (2×8 mL) and 2 M K₂CO₃ (1×5 mL). Theorganic phase was dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was dissolved in DCM (5 mL) andpurified by flash column chromatography to yield the title compound asan orange-yellow foam (328 mg, 57.7% yield).

Step B:(R)-4-oxo-5-(6-phenoxypyridin-3-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(4-oxo-5-(6-phenoxypyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(324 mg, 0.551 mmol) was dissolved in 9:1:0.05 MeOH/CH₃CN/TFA (1 mL) andpurified by C18 HPLC to yield the title compound as a light yellowpowder (302 mg, 94.3% yield).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI, in Example 1, to yield the title compound (80 mg, 36% yield). MS(ESI): mass calcd. for C₂₈H₂₄N₆O₄S, 540.6; m/z found, 541.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD): δ 8.31 (d, J=5.6 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H),7.94 (dd, J=8.7, 2.7 Hz, 1H), 7.49-7.41 (m, 2H), 7.28-7.23 (m, 1H),7.21-7.18 (m, 2H), 7.15 (d, J=8.7 Hz, 1H), 6.84-6.73 (m, 1H), 6.25-6.13(m, 2H), 5.72 (dd, J=23.1, 10.7 Hz, 1H), 4.60-4.49 (m, 0.5H), 4.32 (d,J=12.6 Hz, 0.5H), 4.19 (d, J=11.5 Hz, 0.5H), 4.02-3.86 (m, 1.5H), 3.15(q, J=10.6, 10.1 Hz, 1H), 2.87 (q, J=12.0 Hz, 1H), 2.06 (d, J=12.5 Hz,1H), 1.91-1.80 (m, 1H), 1.77-1.65 (m, 1H), 1.63-1.50 (m, 1H).

Example 507:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3′-chloro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-butyl3-(5-(3′-chloro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

A solution of (R)-tert-butyl3-(5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(Example 504, Step A) (170 mg, 0.30 mmol) (3-chlorophenyl)boronic acid(70 mg, 0.45 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (25 mg, 0.031 mmol), and Na₂CO₃80 mg, (0.76 mmol) in dioxane (7 mL) and H₂O (1 mL) was sparged with N₂and stirred at 120° C. for 4 h. The reaction mixture was cooled andpurified by flash column chromatography to yield the title compound asyellow solid (140 mg, 78% yield).

Step B:(R)-5-(3′-chloro-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(3′-chloro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(140 mg, 0.232 mmol) and concentrated HCl (2 mL) and MeOH (15 mL) wasstirred at room temperature for 2 hours. The reaction was concentratedto dryness and purified by flash column chromatography to yield thetitle compound as yellow solid (130 mg, 87% yield).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3′-chloro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, to yield 43 mg (24% yield). MS (ESI): mass calcd. forC₂₉H₂₄ClN₅O₃S, 558.1; m/z found, 558.5 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 10.15 (s, 1H), 8.29 (d, J=5.5 Hz, 1H), 8.15-8.00 (m, 1H),7.93-7.83 (m, 2H), 7.79-7.72 (m, 1H), 7.70-7.63 (m, 2H), 7.55-7.37 (m,3H), 6.88-6.62 (m, 1H), 6.14-5.95 (m, 2H), 5.69-5.58 (m, 1H), 4.49-4.10(m, 1H), 4.08-3.89 (m, 1H), 3.86-3.70 (m, 1H), 3.15-2.90 (m, 1H),2.84-2.60 (m, 1H), 1.99-1.87 (m, 1H), 1.82-1.55 (m, 2H), 1.51-1.32 (m,1H).

Example 508:N-((3S,4R)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral Resolution Method A to obtain the *S atropisomerafter Step F) in Example 1, and using tert-butyl(3S,4R)-3-amino-4-methoxy-pyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G.MS (ESI): mass calcd. for C₃₀H₂₇N₅O₅S, 569.6; m/z found, 570.4 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ 8.26 (d, J=5.4 Hz, 1H), 7.41-7.30 (m, 2H),7.30-7.22 (m, 1H), 7.14-7.07 m, 1H), 7.06-6.98 (m, 3H), 6.94-6.87 (m,1H), 6.58-6.46 (m, 1H), 6.24-6.11 (m, 1H), 6.02-5.91 (m, 1H), 5.69-5.61(m, 1H), 4.70-4.56 (m, 1H), 4.05-3.72 (m, 3H), 3.70-3.54 (m, 1H),3.49-3.41 (m, 1H), 3.36-3.30 (m, 3H), 2.04 (s, 3H).

Example 509:(R,EZ)—N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98) (300 mg, 0.601 mmol), 2-cyanoacetic acid (102 mg, 1.20mmol), HATU (297 mg, 0.780 mmol), and diisopropylethylamine (155 mg,1.20 mmol) in DMF (5 mL) was stirred at rt for 1 h. The reaction mixturewas purified by flash column chromatography to yield the title compoundas white solid (225 mg, 66.2% yield).

Step B:(R,EZ)—N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(85 mg, 0.15 mmol), 3-methyloxetane-3-carbaldehyde (45 mg, 0.45 mmol),piperidine (0.3 mL), AcOH (0.1 mL), dioxane (5 mL), and 4A molecularsieves (0.3 g) was stirred at 100° C. for 1 h under N₂. The mixture wasconcentrated to dryness and purified by flash column chromatography togive the title compound as white solid (91 mg, 93% yield). MS (ESI):mass calcd. for C₃₅H₃₂N₆O₅S, 648.7; m/z found, 649.4 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.33-8.28 (m, 1H), 7.42-7.35 (m, 2H), 7.32-7.23 (m, 2H),7.18-7.12 (m, 1H), 7.11-7.00 (m, 3H), 6.99-6.93 (m, 1H), 6.06-6.02 (m,1H), 5.02-4.88 (m, 1H), 4.65-4.19 (m, 4H), 4.06-3.59 (m, 3H), 3.57-3.32(m, 1H), 2.14-2.01 (m, 4H), 1.99-1.77 (m, 2H), 1.71-1.58 (m, 4H).

Example 510:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′-chloro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example498, steps A-E, and using2-(2-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in place of(2,3-difluorophenyl)boronic acid in step C. MS (ESI): mass calcd. forC₂₉H₂₄ClN₅O₃S, 558.1; m/z found, 558.1 [M+H]⁺. 1H NMR (400 MHz,DMSO-d6): δ 8.27 (d, J=5.1 Hz, 1H), 8.24-8.08 (m, 1H), 7.73-7.61 (m,1H), 7.60-7.53 (m, 2H), 7.52-7.35 (m, 5H), 6.88-6.62 (m, 1H), 6.13-5.99(m, 2H), 5.70-5.58 (m, 1H), 4.53-4.06 (m, 1H), 4.04-3.87 (m, 1H),3.82-3.69 (m, 1H), 3.10-2.94 (m, 1H), 2.87-2.59 (m, 1H), 2.00-1.85 (m,1H), 1.81-1.52 (m, 2H), 1.46-1.32 (m, 1H).

Example 511:(R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R,E)-tert-buty(4-(3-(5-(S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate

A solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98) (90 mg, 0.18 mmol),(E)-4-(tert-butoxycarbonylamino)but-2-enoic acid (Intermediate 12) (72mg, 0.36 mmol), HATU (89 mg, 0.23 mmol), and diisopropylethylamine (70mg, 0.54 mmol) in DMF (5 mL) was stirred at rt for 1 h. The mixture waspurified by flash column chromatography to give the title compound aswhite solid (101 mg, 82% yield).

Step B:(R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R,E)-tert-butyl(4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate(101 mg, 0.148 mmol), concentrated HCl (5 mL), and MeOH (5 mL) wasstirred at rt for 1 h. The mixture was concentrated to dryness and theresidue was purified by flash column chromatography to give the titlecompound as white solid (67 mg, 95% yield). MS (ESI): mass calcd. forC₃₁H₃₀N₆O₄S, 582.7; m/z found, 583.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆and CD₃OD): δ 8.36 (s, 1H), 8.30-8.25 (m, 1H), 7.40-7.33 (m, 2H),7.29-7.23 (m, 1H), 7.17-7.09 (m, 1H), 7.09-7.00 (m, 3H), 6.96-6.89 (m,1H), 6.75-6.57 (m, 2H), 5.98-5.93 (m, 1H), 4.15-3.77 (m, 3H), 3.63-3.57(m, 2H), 3.13-3.00 (m, 1H), 2.85-2.63 (m, 1H), 2.04 (s, 3H), 2.00-1.89(m, 1H), 1.85-1.74 (m, 1H), 1.74-1.59 (m, 1H), 1.54-1.39 (m, 1H).

Example 512:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 2-phenylpyridin-4-amine in place of2-methyl-4-phenoxy-aniline in step C and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₈H₂₄N₆O₃S, 524.6; m/z found, 525.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 10.27 (s, 1H), 8.92-8.83 (m, 1H), 8.35-8.26 (m, 1H),8.18-8.04 (m, 4H), 7.53-7.42 (m, 4H), 6.84-6.66 (m, 1H), 6.26-6.15 (m,1H), 6.12-6.01 (m, 1H), 5.70-5.59 (m, 1H), 4.50-4.09 (m, 1H), 4.06-3.90(m, 1H), 3.82-3.72 (m, 1H), 3.16-2.92 (m, 1H), 2.84-2.59 (m, 1H),1.96-1.88 (m, 1H), 1.80-1.72 (m, 1H), 1.72-1.55 (m, 1H), 1.47-1.34 (m,1H).

Example 513:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A round bottom flask containing a solution of4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 60, 60.0 g, 148 mmol) in DMF (500 mL) was treatedwith HATU (73.9 g, 193 mmol) and TEA (59.9 g, 593 mmol). The mixture wasstirred for 30 minutes until all of the solids were dissolved.1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) (35.0 g,233 mmol) was added as a suspension in DMF (200 mL). The reactionmixture was stirred at room temperature for 30 min. The mixture wastreated with water (600 mL), the resulting precipitate was collected byfiltration, dried under vacuum, then purified (FCC, SiO₂,MeOH/EtOAc/DCM=1/13/26) to give the title compound (40.0 g, 50%) aslight yellow solid. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₄S, 540.16; m/zfound, 541.0 [M+H]⁺. ¹H NMR (600 MHz, DMSO) δ 10.24 (d, J=17.7 Hz, 1H),8.47-8.41 (m, 1H), 8.36 (d, J=5.5 Hz, 1H), 8.16-8.01 (m, 1H), 7.73-7.68(m, 1H), 7.66-7.61 (m, 1H), 7.54-7.46 (m, 2H), 7.29-7.19 (m, 3H),6.85-6.73 (m, 1H), 6.22 (d, J=5.5 Hz, 1H), 6.11 (d, J=17.5 Hz, 1H),5.72-5.63 (m, 1H), 4.52-4.17 (m, 1H), 4.11-3.94 (m, 1H), 3.85-3.75 (m,1H), 3.17-2.95 (m, 1H), 2.81-2.63 (m, 1H), 2.00-1.92 (m, 1H), 1.82-1.75(m, 1H), 1.74-1.59 (m, 1H), 1.50-1.37 (m, 1H).

Example 514:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (100 mg, 0.2 mmol), (E)-2-cyano-3-cyclopropyl-prop-2-enoicacid (Intermediate 17) (55 mg, 0.40 mmol), HATU (99 mg, 0.26 mmol), anddiisopropylethylamine (77 mg, 0.60 mmol) in DMF (5 mL) was stirred at rtfor 1 h. The reaction mixture was purified by flash columnchromatography to yield the title compound as white solid (63 mg, 98%yield). MS (ESI): mass calcd. for C₃₄H₃₀N₆O₄S, 618.7; m/z found, 619.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆ and CD₃OD): δ 8.31-8.27 (m, 1H),7.41-7.34 (m, 2H), 7.30-7.26 (m, 1H), 7.16-7.10 (m, 1H), 7.08-7.01 (m,3H), 6.95-6.89 (m, 1H), 6.51-6.45 (m, 1H), 5.99-5.95 (m, 1H), 3.99-3.80(m, 3H), 3.12-2.87 (m, 2H), 2.05 (s, 3H), 1.98-1.84 (m, 2H), 1.84-1.75(m, 1H), 1.75-1.62 (m, 1H), 1.62-1.44 (m, 1H), 1.17-1.07 (m, 2H),0.98-0.87 (m, 1H), 0.87-0.75 (m, 1H).

Example 515:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example498, steps A-E, and using (2,4-difluorophenyl)boronic acid in place of(2,3-difluorophenyl)boronic acid in step C, to yield the title compound.MS (ESI): mass calcd. for C₂₉H₂₃F₂N₅O₃S, 559.6; m/z found, 560.6 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): δ10.13 (s, 1H), 8.29 (d, J=5.5 Hz, 1H),8.14-7.98 (m, 1H), 7.76-7.57 (m, 4H), 7.52-7.44 (m, 1H), 7.4-7.30 (m,1H), 7.25-7.13 (m, 1H), 6.87-6.62 (m, 1H), 6.19-6.01 (m, 2H), 5.68-5.55(m, 1H), 4.56-4.10 (m, 1H), 4.05-3.87 (m, 1H), 3.82-3.71 (m, 1H),3.18-2.88 (m, 1H), 2.83-2.57 (m, 1H), 2.01-1.83 (m, 1H), 1.80-1.55 (m,2H), 1.48-1.29 (m, 1H).

Example 516:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-benzylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-(3-benzylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared using the procedure found in Example506, step A, and using 3-benzylaniline in place of6-phenoxypyridin-3-amine to yield the title compound (122 mg).

Step B:(R)-5-(3-Benzylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(3-benzylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(119.8 mg, 0.205 mmol) in dioxane (1.0 mL) was treated with HCl (4 M indioxane, 2.55 mL) in one portion at rt, and was stirred at rt for 1 h.The reaction mixture was concentrated to dryness to yield the titlecompound as a yellow-beige powder (114 mg, 98.0% yield).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-benzylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI, in Example 1. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₃S, 537.6; m/zfound, 538.2 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6, 1.2:1 mixture ofrotamers) δ 10.17 (br. s., 1H), 8.32 (d, J=5.56 Hz, 1H), 8.05-8.16 (m,1H), 7.49-7.56 (m, 1H), 7.40 (d, J=7.58 Hz, 1H), 7.24-7.37 (m, 6H),7.17-7.24 (m, 1H), 6.73-6.88 (m, 1H), 6.11 (d, J=16.17 Hz, 1H), 5.97 (d,J=5.56 Hz, 1H), 5.69 (d, J=12.13 Hz, 1H), 4.41-4.55 (m, 0.5H), 4.15-4.29(m, 0.5H), 3.95-4.13 (m, 3H), 3.72-3.88 (m, 1H), 2.91-3.17 (m, 1H),2.59-2.83 (m, 1H), 1.88-1.98 (m, 1H), 1.74-1.85 (m, 1H), 1.57-1.74 (m,1H), 1.34-1.53 (m, 1H).

Example 517:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3′-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example498, steps A-E, and using m-tolylboronic acid in place of(2,3-difluorophenyl)boronic acid in step C. MS (ESI): mass calcd. forC₃₀H₂₇N₅O₃S, 537.6; m/z found, 538.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.28 (d, J=5.5 Hz, 1H), 7.80-7.75 (m, 1H), 7.70-7.62 (m, 2H), 7.50-7.35(m, 3H), 7.34-7.26 (m, 1H), 7.19-7.13 (m, 1H), 6.83-6.69 (m, 1H),6.24-6.11 (m, 2H), 5.76-5.64 m, 1H), 4.34-4.23 (m, 1H), 4.21-4.11 (m,1H), 4.06-3.87 (m, 2H), 3.20-3.12 (m, 1H), 2.94-2.85 (m, 1H), 2.37 (s,3H), 2.08-2.02 (m, 1H), 1.88-1.81 (m, 1H), 1.76-1.66 (m, 1H), 1.60-1.49(m, 1H).

Example 518:(S)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral Resolution Method A to obtain the *S atropisomerafter Step F) in Example 1, and using tert-butyl(3S)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₉H₂₅N₅O₄S, 539.6; m/z found, 540.4 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆ and CD₃OD): δ 8.30-8.26 (m, 1H), 7.39-7.32 (m, 2H),7.29-7.24 (m, 1H), 7.15-7.09 (m, 1H), 7.07-6.99 (m, 3H), 6.94-6.89 (m,1H), 6.62-6.46 (m, 1H), 6.20-6.12 (m, 1H), 6.00-5.95 (m, 1H), 5.68-5.62(m, 1H), 4.60-4.45 (m, 1H), 3.93-3.39 (m, 4H), 2.26-1.93 (m, 5H).

Example 519:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclohexylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 3-Cyclohexylaniline

A solution of 1-bromo-3-nitro-benzene (2.50 g, 12.4 mmol),cyclohexen-1-ylboronic acid (1.56 g, 12.4 mmol), Pd(dppf)Cl₂ (505 mg,0.619 mmol)), and Na₂CO₃ (2.62 g, 24.8 mmol) in dioxane (50 mL) and H₂O(5 mL) was stirred at 110° C. overnight. The reaction mixture wasconcentrated to dryness and the residue was purified by flash columnchromatography to give the intermediate as a yellow solid. To theintermediate in EtOH (50 mL) at rt was added Pd/C (1.0 g). The mixturewas flushed with H₂ (2×) and stirred at rt for 16 h. The reactionmixture was filtered and the filtrate was concentrated to dryness togive the title compound (1.6 g, 74% yield), which was used withoutfurther

Step B: Methyl5-(3-cyclohexylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

A solution of 2-chloro-4-iodo-pyridine-3-carbonitrile (1.60 g, 6.05mmol), 3-cyclohexylaniline (1.06, 6.05 mmol), Pd(OAc)₂ (134 mg, 0.600mmol), DPEphos (646 mg, 1.20 mmol), and Cs₂CO₃ (3.93 g, 12.1 mmol) indioxane (100 mL) was heated at reflux under N₂ overnight. Methyl2-sulfanylacetate (0.955 g, 9.00 mmol) was added and stirred at refluxovernight. CDI (2.92 g, 18.0 mmol) was added and stirred at refluxovernight. The reaction mixture was concentrated to dryness and theresidue was purified by flash column chromatography to give the titlecompound as a pale yellow solid (900 mg, 36.5% yield).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclohexylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsE-I in Example 1, using methyl5-(3-cyclohexylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylateand using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G.MS (ESI): mass calcd. for C₂₉H₃₁N₅O₃S, 529.7; m/z found, 530.6 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ 8.19 (d, J=5.4 Hz, 1H), 7.50-7.44 (m, 1H),7.38-7.34 (m, 1H), 7.32-7.27 (m, 1H), 7.26-7.19 (m, 1H), 6.82-6.68 (m,1H), 6.22-6.09 (m, 1H), 5.99 (d, J=5.6 Hz, 1H), 5.74-5.59 (m, 1H),4.55-4.28 (m, 1H), 4.25-3.87 (m, 2H), 3.19-3.03 (m, 1H), 2.88-2.75 (m,1H), 2.62-2.52 (m, 1H), 2.08-1.99 (m, 1H), 1.91-1.78 (m, 5H), 1.75-1.64(m, 2H), 1.56-1.34 (m, 5H), 1.30-1.20 (m, 1H).

Example 520:(R,E)-N-(1-(4-Aminobut-2-enoyl)pyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared analogous to Example 511 using(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 36) instead of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98) to yield a white solid (67 mg, 71% yield). MS (ESI): masscalcd. for C₃₀H₂₈N₆O₄S, 568.6; m/z found, 569.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.47 (s, 1H), 8.36-8.29 (m, 1H), 7.44-7.35 (m, 2H), 7.33-7.26(m, 1H), 7.21-7.13 (m, 1H), 7.13-7.02 (m, 3H), 7.01-6.93 (m, 1H),6.85-6.74 (m, 1H), 6.66-6.54 (m, 1H), 6.11-6.04 (m, 1H), 4.06-3.46 (m,7H), 2.40-2.05 (m, 5H).

Example 521:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4′-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example498, steps A-E, and using p-tolylboronic acid in place of(2,3-difluorophenyl)boronic acid in step C. MS (ESI): mass calcd. forC₃₀H₂₇N₅O₃S, 537.6; m/z found, 538.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.25 (d, J=5.6 Hz, 1H), 7.79-7.73 (m, 1H), 7.70-7.60 (m, 2H), 7.56-7.49(m, 2H), 7.39-7.32 (m, 1H), 7.27-7.19 (m, 2H), 6.83-6.70 (m, 1H),6.24-6.11 (m, 2H), 5.78-5.64 (m, 1H), 4.52-4.45 (m, 1H), 4.34-4.11 (m,1H), 4.00-3.88 (m, 1H), 3.21-3.10 (m, 1H), 2.96-2.82 (m, 1H), 2.34 (s,3H), 2.12-1.99 (m, 1H), 1.90-1.80 (m, 1H), 1.79-1.65 (m, 1H), 1.62-1.49(m, 1H).

Example 522:(R,E)-N-(1-(4-Hydroxybut-2-enoyl)pyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*S)(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 36, 100 mg, 0.192 mmol), (E)-4-hydroxybut-2-enoic acid(Intermediate 13, 29 mg, 0.286 mmol), HATU (146 mg, 0.384 mmol), andtriethylamine (97 mg, 0.96 mmol) in DMF (3 mL) was stirred at rt for 2h, then purified by flash column chromatography to give the titlecompound as a light yellow solid (55 mg, 49% yield). MS (ESI): masscalcd. for C₃₀H₂₇N₅O₅S, 569.6; m/z found, 570.5 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.31 (d, J=5.5 Hz, 1H), 7.45-7.34 (m, 2H), 7.29 (d, J=8.6 Hz,1H), 7.20-7.12 (m, 1H), 7.12-7.01 (m, 3H), 6.98-6.85 (m, 2H), 6.55-6.37(m, 1H), 6.05 (d, J=5.6 Hz, 1H), 4.69-4.56 (m, 1H), 4.32-4.20 (m, 2H),4.00-3.46 (m, 4H), 2.40-2.20

Example 523:N-((3S,4S)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral Resolution Method A to obtain the *S atropisomerafter Step F) in Example 1, and using tert-butyl(3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (Intermediate 24) inplace of tert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate instep G, to yield the title compound. MS (ESI): mass calcd. forC₂₉H₂₅N₅O₅S, 555.6; m/z found, 556.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 10.15 (br, 1H), 8.36-8.24 (m, 2H), 7.46-7.38 (m, 2H), 7.37-7.31 (m,1H), 7.21-7.14 (m, 1H), 7.13-7.04 (m, 3H), 6.98-6.93 (m, 1H), 6.61-6.51(m, 1H), 6.17-6.09 (m, 1H), 5.98-5.92 (m, 1H), 5.68-5.62 (m, 1H),5.49-5.37 (m, 1H), 4.33-4.11 (m, 2H), 3.94-3.39 (m, 4H), 2.03 (s, 3H).

Example 524:5-(*S)-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((S)-2-(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid(98 mg, 0.48 mmol), HATU (182 mg, 0.48 mmol), and triethylamine (202 mg,2.00 mmol) were dissolved in anhydrous DMF (5 mL) and stirred at roomtemperature. After 10 min,(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98) (200 mg, 0.40 mmol) was added and the mixture was stirredfor 2 h. The crude mixture was purified by flash column chromatographyto get a white solid. The solid was diluted in 6.0 N HCl/MeOH, thenconcentrated to dryness. The residue was purified by flash columnchromatography to give the title compound as a light yellow solid (125mg, 48.0% yield). MS (ESI): mass calcd. for C₃₁H₃₂N₆O₄S, 584.7; m/zfound, 585.6 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.49 (s, 1H), 8.35-8.20(m, 1H), 7.45-7.33 (m, 2H), 7.30-7.22 (m, 1H), 7.20-7.12 (m, 1H),7.11-7.02 (m, 3H), 7.00-6.93 (m, 1H), 6.11-5.96 (m, 1H), 4.54-4.05 (m,2H), 4.03-3.67 (m, 2H), 3.25-2.85 (m, 2H), 2.65-2.53 (m, 3H), 2.14-2.07(m, 3H), 2.04-1.65 (m, 3H), 1.64-1.38 (m, 4H).

Example 525:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(3-amino-4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate

To a Biotage vial were added 2-chloro-4-iodonicotinonitrile (1.03 g,3.90 mmol), 2,2-difluoro-5-aminobenzodioxole (710 mg, 3.90 mmol),bis(2-diphenylphosphinophenyl)ether (64 mg, 0.12 mmol), palladium(II)acetate (17 mg, 0.078 mmol), Cs₂CO₃ (1.777 g, 5.453 mmol), and dioxane(7.8 mL) and was stirred at rt while purging with N₂ stream for 30 min,then it was placed in heating block at 110° C. for 1.5 h. Next,tert-butyl (3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate(Intermediate 22) (6.0 mL, 3.9 mmol) was added and it was purged with N₂for 15 min, then was heated at 90° C. for 1.5 hr. The reaction mixturewas diluted with EtOAc, filtered through Celite, concentrated todryness, and purified by flash column chromatography to give the titlecompound as a yellow oil (1.715 g, 80.43% yield).

Step B: (R)-tert-Butyl3-(5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate.To a 40 mL vial were added (R)-tert-butyl3-(3-amino-4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate(1.5 g, 2.7 mmol), acetonitrile (5.5 mL), Cs₂CO₃ (1.34 g, 4.11 mmol),CDI (888 mg, 5.48 mmol) and was stirred at 75° C. for 1.5 h. After 1.5h, more CDI (888 mg, 5.48 mmol) was added and was heated for anadditional 50 min. The reaction mixture was diluted with EtOAc andH₂O/brine, the organic layer was collected, dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness. The residue was purified by flashcolumn chromatography to give the title compound as a brown oil (1.587g, 89.1% yield) Step C:(R)-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a 40 mL round bottom flask were added (R)-tert-butyl3-(5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(562 mg, 0.98 mmol), DCM (1.96 mL), and TFA (0.38 mL, 5.0 mmol) and wasstirred at rt for 15 min, then DCE (1.96 mL) was added and was heated at40° C. for 20 min. Another 5 equivalents of TFA 0.38 mL) was added andwas heated at 50° C. for 20 min. The reaction was quenched withsaturated aqueous NaHCO₃, diluted with DCM, and the organic layer wascollected. EtOAc was added to the aqueous phase and the organic phasecollected. The aqueous phase was extracted again with 5% MeOH in EtOAc.The combined organic phases were dried over anhydrous Na₂SO₄, filtered,concentrated to dryness to yield the title compound as a yellow foam(6.60 mg).

Step D:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1. MS (ESI): mass calcd. for C₂₄H₁₉F₂N₅O₅S, 527.5; m/zfound, 528.0 [M+H]+. ¹H NMR (500 MHz, CD₃OD): δ 8.31 (d, J=5.6 Hz, 1H),7.44 (d, J=8.4 Hz, 2H), 7.30 (dd, J=8.5, 2.0 Hz, 1H), 6.86-6.73 (m, 1H),6.25-6.17 (m, 2H), 5.78-5.68 (m, 1H), 4.58-4.51 (m, 0.5H), 4.32 (d,J=13.5 Hz, 0.5H), 4.22-4.15 (m, 0.5H), 4.04-3.92 (m, 1.5H), 3.17 (t,J=11.5 Hz, 1H), 2.96-2.83 (m, 1H), 2.07 (d, J=12.8 Hz, 1H), 1.92-1.83(m, 1H), 1.78-1.67 (m, 1H), 1.64-1.53 (m, 1H).

Example 526:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenylpyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 4-phenylpyridin-2-amine in Step C andtert-butyl (3R)-3-aminopiperidine-1-carboxylate Step G. MS (ESI): masscalcd. for C₂₈H₂₄N₆O₃S, 524.6; m/z found, 525.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.75-8.66 (m, 1H), 8.34-8.30 (m, 1H), 7.96-7.91 (m, 1H),7.90-7.85 (m, 1H), 7.83-7.78 (m, 2H), 7.54-7.44 (m, 3H), 6.84-6.69 (m,1H), 6.28-6.22 (m, 1H), 6.21-6.12 (m, 1H), 5.77-5.65 (m, 1H), 4.35-3.86(m, 3H), 3.21-3.09 (m, 1H), 3.00-2.81 (m, 1H), 2.13-1.97 (m, 1H),1.93-1.80 (m, 1H), 1.78-1.65 (m, 1H), 1.62-1.49 (m, 1H).

Example 527:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analagous to Example 506, using3-phenoxyaniline in place of 6-phenoxypyridin-3-amine in step A. MS(ESI): mass calcd. for C₂₉H₂₅N₅O₄S, 539.6; m/z found, 540.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 10.18 (br. s., 1H), 8.35 (d, J=5.56 Hz, 1H),8.03-8.15 (m, 1H), 7.61 (t, J=8.08 Hz, 1H), 7.40-7.47 (m, 2H), 7.24 (d,J=8.59 Hz, 1H), 7.15-7.22 (m, 3H), 7.09-7.15 (m, 2H), 6.72-6.88 (m, 1H),6.06-6.16 (m, 2H), 5.65-5.73 (m, 1H), 4.43-4.52 (m, 0.5H), 4.17-4.27 (m,0.5H), 3.94-4.11 (m, 1H), 3.72-3.84 (m, 1H), 3.04-3.15 (m, 0.5H),2.92-3.04 (m, 0.5H), 2.71-2.84 (m, 0.5H), 2.60-2.70 (m, 0.5H), 1.88-1.98(m, 1H), 1.73-1.84 (m, 1H), 1.57-1.73 (m, 1H), 1.35-1.51 (m, 1H).

Example 528:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyrazin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 5-Phenoxypyrazin-2-amine

A mixture of phenol (1.75 g, 18.6 mmol), 5-bromopyrazin-2-amine (3.0 g,17 mmol), Cs₂CO₃ (7.85 g, 24.1 mmol), CuI (330 mg, 1.72 mmol),N,N-dimethylglycine (180 mg, 1.75 mmol) in dioxane was sparged with N₂and heated to 115° C. under N₂ for 2 h. After cooling to roomtemperature, the mixture was purified by flash column chromatography togive the title compound as a yellow solid (2.0 g, 62% yield).

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyrazin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 5-phenoxypyrazin-2-amine in place of2-methyl-4-phenoxy-aniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₇H₂₃N₇O₄S, 541.6; m/z found, 542.7 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.51-8.44 (m, 1H), 8.38-8.26 (m, 2H), 7.52-7.39 (m, 2H),7.33-7.20 (m, 3H), 6.86-6.70 (m, 1H), 6.39-6.31 (m, 1H), 6.25-6.11 (m,1H), 5.80-5.65 (m, 1H), 4.57-3.85 (m, 3H), 3.22-3.10 (m, 1H), 2.99-2.79(m, 1H), 2.14-2.00 (m, 1H), 1.91-1.81 (m, 1H), 1.8-1.66 (m, 1H),1.64-1.50 (m, 1H).

Example 529:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-isopropylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsE-I in Example 1, using 3-isopropylaniline in Step C, and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₆H₂₇N₅O₃S, 489.6; m/z found, 490.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.32-8.26 (m, 1H), 7.57-7.48 (m, 1H), 7.46-7.39 (m, 1H),7.33-7.28 (m, 1H), 7.23-7.19 (m, 1H), 6.83-6.74 (m, 1H), 6.27-6.15 (m,1H), 6.11-6.05 (m, 1H), 5.79-5.67 (m, 1H), 4.43-4.18 (m, 1H), 4.18-3.90(m, 2H), 3.24-3.10 (m, 1H), 3.03-2.83 (m, 2H), 2.12-1.99 (m, 1H),1.91-1.82 (m, 1H), 1.77-1.66 (m, 1H), 1.65-1.51 (m, 1H) 1.31-1.26 (m,6H).

Example 530:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(vinylsulfonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-butyl3-(5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared in a manner analogous to Method 1, stepsA-G (including Chiral Resolution Method A to obtain the *S atropisomerafter Step F) in Example 1, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G.

Step B:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(vinylsulfonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(100 mg, 0.167 mmol) in 6 M HCl (15 mL, in MeOH) was concentrated todryness to get a yellow solid. The residue was diluted in DCM (30 mL)and triethylamine (84 mg, 0.84 mmol) was added, followed byethenesulfonyl chloride (21 mg, 0.17 mmol). The reaction was stirred atrt for 1 h, then concentrated to dryness and purified by flash columnchromatography to give the title compound as a white yellow solid (54mg, 54% yield). MS (ESI): mass calcd. for C₂₉H₂₇N₅O₅S₂, 589.7; m/zfound, 590.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d, J=5.6 Hz, 1H),7.49-7.34 (m, 2H), 7.33-7.25 (m, 1H), 7.24-7.14 (m, 1H), 7.13-7.02 (m,3H), 7.00-6.93 (m, 1H), 6.74-6.57 (m, 1H), 6.18 (d, J=16.6 Hz, 1H),6.13-6.02 (m, 2H), 4.14-4.00 (m, 1H), 3.83-3.68 (m, 1H), 3.63-3.47 (m,1H), 2.79-2.58 (m, 2H), 2.12 (s, 3H), 2.03-1.85 (m, 2H), 1.75-1.64 (m,1H), 1.63-1.50 (m, 1H).

Example 531:(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-acryloylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using [1,1′-biphenyl]-3-amine (Intermediate 46) inplace of 2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₈H₂₃N₅O₃S, 509.6; m/z found, 510.9 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.26 (d, J=5.6 Hz, 1H), 7.82-7.76 (m, 1H), 7.73-7.58 (m,4H), 7.49-7.30 (m, 4H), 6.68-6.50 (m, 1H), 6.32-6.21 (m, 1H), 6.15 (d,J=5.6 Hz, 1H), 5.78-5.65 (m, 1H), 4.67-4.55 (m, 1H), 4.00-3.45 (m, 4H),2.37-2.18 (m, 1H), 2.17-1.97 (m, 1H).

Example 532:(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylsulfonamido)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R,E)-N-(1-(4-aminobut-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 520) (157 mg, 0.269 mmol) and triethylamine (55 mg, 0.54 mmol)in DCM (10 mL) was added methanesulfonyl chloride (31 mg, 0.27 mmol) andwas stirred at room temperature for 15 minutes. The mixture wasdispersed between DCM and water, and the organic layer was collected,concentrated to dryness, and purified by flash column chromatography,then by preparative TLC to give the title compound (137 mg, 76.0%yield). MS (ESI): mass calcd. for C₃₂H₃₂N₆O₆S₂, 660.8; m/z found, 661.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.17 (s, 1H), 8.35-8.28 (m, 1H),8.13-7.99 (m, 1H), 7.45-7.39 (m, 2H), 7.38-7.33 (m, 1H), 7.32-7.27 (m,1H), 7.20-7.15 (m, 1H), 7.13-7.08 (m, 2H), 7.08-7.04 (m, 1H), 6.99-6.92(m, 1H), 6.64-6.55 (m, 2H), 6.00-5.91 (m, 1H), 4.51-4.12 (m, 1H),4.04-3.92 (m, 1H), 3.79-3.71 (m, 3H), 3.11-2.90 (m, 1H), 2.88 (s, 3H),2.76-2.58 (m, 1H), 2.04 (s, 3H), 1.95-1.88 (m, 1H), 1.80-1.70 (m, 1H),1.69-1.56 (m, 1H), 1.46-1.33 (m, 1H).

Example 533:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-propylphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 3-propyl aniline in Step C tert-butyl(3R)-3-aminopiperidine-1-carboxylate in Step G. MS (ESI): mass calcd.for C₂₆H₂₇N₅O₃S, 489.6; m/z found, 491.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.29-8.26 (d, J=5.6 Hz, 1H), 7.53-7.47 (m, 1H), 7.39-7.35 (m,1H), 7.27-7.20 (m, 2H), 6.84-6.74 (m, 1H), 6.23-6.15 (m, 1H), 6.09-6.06(m, 1H), 5.76-5.68 (m, 1H), 4.56-4.26 (m, 1H), 4.20-3.92 (m, 2H),3.21-3.12 (m, 1H), 2.95-2.83 (m, 1H), 2.68 (t, J=7.6 Hz, 2H), 2.10-2.02(m, 1H), 1.90-1.82 (m, 1H), 1.77-1.63 (m, 3H), 1.62-1.53 (m, 1H), 0.96(t, J=7.3 Hz, 3H).

Example 534:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclobutylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-(3-cyclobutylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a microwave vial containing a stir bar,2-chloro-4-iodo-pyridine-3-carbonitrile (1.152 g, 4.356 mmol) and3-cyclobutylaniline (636 mg, 4.32 mmol) were added DPEphos (126 mg,0.234 mmol), Pd(OAc)₂ (40.6 mg, 0.181 mmol), and Cs₂CO₃ (2.22 g, 6.81mmol). Dioxane (10 mL) was added to the reaction mixture via syringe andwas degassed under vacuum for 1 minute, then vented to nitrogen. Thereaction mixture was heated at 130° C. for 60 minutes. The reaction wascooled to rt and treated with tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate22) (1.5 g, 0.411 mmol) as a solution in dioxane (6 mL), and wasevacuated and then flushed with nitrogen. The reaction was then stirredat 130° C. for 1 h followed by treatment with solid CDI (2.19 g, 13.5mmol) in one portion, resealed, and stirred at 90° C. for 30 min. Thereaction was diluted with EtOAc (100 mL) and saturated aqueous sodiumbicarbonate (100 mL), and the organic phase collected. The aqueous layerwas extracted with EtOAc (100 mL), and the combined organics were driedover anhydrous MgSO₄, concentrated to dryness, and purified by flashcolumn chromatography to give the title compound as an off white solid(1.49 g, 62.3% yield).

Step B:(R)-5-(3-Cyclobutylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(3-cyclobutylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(1.163 g, 2.124 mmol) in dioxane (11 mL) was treated with 4 MHCl-dioxane (11 mL). The reaction mixture was stirred at roomtemperature for 2.5 h. Et₂O (20 mL) was added and the yellow precipitatethat formed was isolated by filtration and dried overnight under vacuumto give the title compound (858.5 mg, 77.68% yield).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclobutylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1. MS (ESI): mass calcd. for C₂₇H₂₇N₅O₃S, 501.6; m/z found,502.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD): δ 8.35-8.23 (d, J=5.5 Hz, 1H),7.59-7.50 (m, 1H), 7.46-7.38 (d, J=7.8 Hz, 1H), 7.33-7.27 (s, 1H),7.25-7.19 (d, J=7.8 Hz, 1H), 6.85-6.74 (m, 1H), 6.26-6.17 (m, 1H),6.15-6.07 (d, J=5.6 Hz, 1H), 5.80-5.68 (m, 1H), 4.60-4.27 (m, 1H),4.23-3.92 (m, 2H), 3.71-3.62 (m, 1H), 3.24-3.12 (m, 1H), 3.00-2.83 (m,1H), 2.45-2.32 (m, 2H), 2.27-2.16 (m, 2H), 2.14-2.02 (m, 2H), 1.96-1.83(m, 2H), 1.81-1.70 (m, 1H), 1.67-1.52 (m, 1H).

Example 535:(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-trideuteriomethylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98) (100 mg, 0.187 mmol) and dideuterioformaldehyde (1.1 mL, 37wt. % in H₂O) in MeOH (2.5 mL) was stirred at rt for 3 h. Sodiumcyanoborodeuteride (49 mg, 0.74 mmol) was added and the mixture wasstirred at rt for 2 h. The concentrated to dryness and the residue waspurified by preparative TLC to give the title compound as a yellow solid(65 mg, 97% yield). MS (ESI): mass calcd. for C₂₈H₂₄D₃N₅O₃S, 516.6; m/zfound, 517.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d, J=5.6 Hz, 1H),7.45-7.33 (m, 2H), 7.33-7.25 (m, 1H), 7.23-7.12 (m, 1H), 7.10-7.02 (m,3H), 6.99-6.91 (m, 1H), 6.06 (d, J=5.5 Hz, 1H), 4.28-4.16 (m, 1H),3.37-3.32 (m, 1H), 3.18-3.05 (m, 1H), 2.76-2.58 (m, 2H), 2.10 (s, 3H),2.03-1.93 (m, 2H), 1.84-1.72 (m, 1H), 1.70-1.58 (m, 1H).

Example 536:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-C, and using 2-methyl-4-phenoxy-aniline in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₄S,553.6; m/z found, 554.1 [M+H]⁺. 1H NMR (400 MHz, MeOD) δ 8.33 (d, J=5.6Hz, 1H), 7.43-7.33 (m, 3H), 7.22 (d, J=8.5 Hz, 1H), 7.17-7.09 (m, 1H),7.06-7.00 (m, 3H), 6.87-6.75 (m, 1H), 6.27-6.15 (m, 2H), 5.80-5.70 (m,1H), 4.59-4.27 (m, 1H), 4.22-3.92 (m, 2H), 3.24-3.12 (m, 1H), 3.01-2.85(m, 1H), 2.32 (s, 3H), 2.15-2.03 (m, 1H), 1.95-1.51 (m, 3H).

Example 537:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenylpyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using step A in the procedure found inExample 526, using 5-phenylpyridin-3-amine in place of4-phenylpyridin-2-amine, and using Method 1, steps E-I in Example 1, andusing tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G,to yield the title compound. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₃S,524.6; m/z found, 525.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 9.05-8.92 (m,1H), 8.70-8.54 (m, 1H), 8.40-8.28 (m, 1H), 8.28-8.22 (m, 1H), 7.77-7.66(m, 2H), 7.55-7.41 (m, 3H), 6.83-6.69 (m, 1H), 6.29-6.22 (m, 1H),6.21-6.15 (m, 1H), 5.79-5.65 (m, 1H), 4.31-3.88 (m, 3H), 3.22-3.06 (m,1H), 2.96-2.82 (m, 1H), 2.10-1.98 (m, 1H), 1.93-1.81 (m, 1H), 176-1.65(m, 1H), 1.61-1.51 (m, 1H).

Example 538:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(pyridin-3-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 3-(3-pyridyl)aniline in place of2-methyl-4-phenoxy-aniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₈H₂₄N₆O₃S, 524.6; m/z found, 525.4 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.87 (s, 1H), 8.61-8.47 (m, 1H), 8.37-8.25 (m, 1H),8.22-8.08 (m, 1H), 7.95-7.68 (m, 3H), 7.60-7.46 (m, 2H), 6.89-6.69 (m,1H), 6.27-6.12 (m, 2H), 5.82-5.64 (m, 1H), 4.56-4.49 (m, 1H), 4.36-4.13(m, 1H), 4.02-3.90 (m, 1H), 3.24-3.10 (m, 1H), 2.98-2.83 (m, 1H),2.13-1.96 (m, 1H), 1.92-1.83 (m, 1H), 1.79-1.67 (m, 1H), 1.64-1.51 (m,1H).

Example 539:(R)—N-(1-(Ethylsulfonyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using steps A-B in the procedure foundin Example 530, using ethanesulfonyl chloride in step B. MS (ESI): masscalcd. for C₂₉H₂₉N₅O₅S₂, 591.7; m/z found, 592.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD and DMSO-d₆): δ 8.29-8.23 (m, 1H), 7.39-7.33 (m, 2H),7.29-7.24 (m, 1H), 7.14-7.09 (m, 1H), 7.06-7.02 (m, 2H), 7.02-6.99 (m,1H), 6.92-6.89 (m, 1H), 5.95-5.91 (m, 1H), 3.92-3.84 (m, 1H), 3.72-3.67(m, 1H), 3.54-3.47 (m, 1H), 2.97 (q, J=7.4 Hz, 2H), 2.78-2.71 (m, 1H),2.71-2.65 (m, 1H), 2.02 (s, 3H), 1.92-1.85 (m, 1H), 1.81-1.73 (m, 1H),1.57-1.48 (m, 2H), 1.18 (t, J=7.3 Hz, 3H).

Example 540:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(pyridin-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

A solution of5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 57) (1.5 g, 3.8 mmol), tert-butyl(3R)-3-aminopiperidine-1-carboxylate (0.77 g, 3.8 mmol), triethylamine(0.78 g, 7.7 mmol), and HATU (1.46 g, 3.84 mmol) in DMF (5 mL) wasstirred at rt for 3 h. Water was added and the precipitate was filteredto give the title compound a pale yellow solid (1.6 g, 73% yield).

Step B:(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(pyridin-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(400 mg, 0.70 mmol), trimethyl(2-pyridyl)silane (186 mg, 0.770 mmol),and Pd(PPh₃)₄ (40 mg, 0.035 mmol) in DMF (5 mL) was stirred at 110° C.for 2 h. The reaction mixture was concentrated to dryness and theresidue was purified by flash column chromatography to get theintermediate as a yellow solid. The solid was dissolved in MeOH (4 mL)and saturated aqueous HCl (4 mL), and the resulting mixture was heatedto 50° C. for 30 min. The reaction mixture was concentrated to drynessand was purified by flash column chromatography to give the titlecompound (240 mg, 73% yield).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(pyridin-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, using(R)-4-oxo-N-(piperidin-3-yl)-5-(3-(pyridin-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamideto yield the title compound. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₃S,524.6; m/z found, 525.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.61-8.54 (m,1H), 8.20 (d, J=5.6 Hz, 1H), 8.16-8.07 (m, 2H), 7.91-7.77 (m, 2H),7.71-7.63 (m, 1H), 7.56-7.48 (m, 1H), 7.35-7.25 (m, 1H), 6.82-6.68 (m,1H), 6.23-6.09 (m, 2H), 5.76-5.60 (m, 1H), 4.58-4.16 (m, 2H), 3.97-3.89(m, 1H), 3.17-3.04 (m, 1H), 2.93-2.74 (m, 1H), 2.08-2.01 (m, 1H),1.85-1.76 (m, 1H), 1.74-1.62 (m, 1H), 1.56-1.44 (m, 1H).

Example 541:(R,E)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(4-(dimethylamino)but-2-enol)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using a method analogous to Example 75,using (E)-4-(dimethylamino)but-2-enoic acid and(R)-5-(3-Chloro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 581) to yield the title compound. MS (ESI): mass calcd. forC₃₂H₃₁ClN₆O₄S, 631.1; m/z found, 631.6 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):δ 8.41 (s, 1H), 8.37-8.27 (m, 1H), 7.77-7.60 (m, 1H), 7.48-7.31 (m, 3H),7.25-7.10 (m, 2H), 7.09-6.89 (m, 2H), 6.92-6.78 (m, 1H), 6.77-6.60 (m,1H), 6.32-6.18 (m, 1H), 4.54-3.86 (m, 3H), 3.78-3.60 (m, 2H), 3.25-3.06(m, 1H), 2.98-2.80 (m, 1H), 2.77-2.60 (m, 6H), 2.15-1.97 (m, 1H),1.95-1.83 (m, 1H), 1.81-1.46 (m, 2H).

Example 542:(R)—N-(1-Isopropylpiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98) (90 mg, 0.18), MeOH (2 mL), and acetone (3 mL) was addedsodium triacetoxyborohydride (76 mg, 0.36 mmol). The reaction mixturewas maintained at room temperature overnight, then concentrated todryness, and purified by flash column chromatography to give the titlecompound as yellow solid (75 mg, 71% yield). MS (ESI): mass calcd. forC₃₀H₃₁N₅O₃S, 541.7; m/z found, 542.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.48 (s, 1H), 8.33 (d, J=5.6 Hz, 1H), 7.46-7.36 (m, 2H), 7.33-7.26 (m,1H), 7.21-7.14 (m, 1H), 7.12-7.04 (m, 3H), 7.01-6.93 (m, 1H), 6.07 (d,J=5.6 Hz, 1H), 4.40-4.26 (m, 1H), 3.54-3.40 (m, 2H), 3.36-3.31 (m, 1H),3.01-2.79 (m, 2H), 2.11 (s, 3H), 2.09-2.01 (m, 2H), 1.95-1.80 (m, 1H),1.76-1.64 (m, 1H), 1.39-1.31 (m, 6H).

Example 543:N-((3S,4S)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (3S,4S)-tert-Butyl3-fluoro-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidine-1-carboxylate

To a solution of (3S,4S)-tert-butyl3-amino-4-fluoropyrrolidine-1-carboxylate (11.85 mL, 1.185 mmol),diisopropylethylamine (0.622 mL, 3.56 mmol), and THF (5 mL) at 0° C. wasadded4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride (Intermediate 40) (0.500 g, 1.19 mmol) dropwise and stirred for30 min. The reaction was quenched with saturated NaHCO₃, extracted withDCM, concentrated to dryness, and the residue was purified by flashcolumn chromatography to give the title compound as an off white solid(480 mg, 69% yield).

Step B:N-((3S,4S)-4-Fluoropyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-45-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (3S,4S)-tert-butyl3-fluoro-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidine-1-carboxylate(400 mg, 0.68 mmol) in DCM (20 mL) was added TFA (11 mL) dropwise at rtand was stirred at rt for an additional 30 min. The reaction wasconcentrated to dryness and the residue was purified by flash columnchromatography to give the title compound as an off white solid (300 mg,90% yield).

Step C:N-((3S,4S)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, usingN-((3S,4S)-4-fluoropyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.MS (ESI): mass calcd. for C₂₈H₂₂FN₅O₄S, 543.6; m/z found, 544.0 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): δ 9.63 (s, 1H), 8.28 (dd, J=5.5, 2.1 Hz, 1H),8.03-7.96 (m, 1H), 7.44-7.28 (m, 4H), 7.22-7.06 (m, 5H), 6.36 (dd,J=7.2, 5.0 Hz, 1H), 6.10 (d, J=5.5 Hz, 1H), 5.72 (td, J=8.3, 4.5 Hz,1H), 5.34-5.22 (m, 1H), 4.84 (dt, J=11.5, 6.0 Hz, 1H), 4.67 (dt, J=10.8,5.2 Hz, 1H), 4.05-3.69 (m, 4H).

Example 544:(S)-1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)pyrrolidine-3-carboxamide

Step A: (S)-tert-Butyl3-((5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)carbamoyl)pyrrolidine-1-carboxylate

A solution of (3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid(33.3 mg, 0.155 mmol), HATU (73.6 mg, 0.194 mmol), and triethylamine (39mg, 0.39 mmol) in anhydrous DMF (3 mL) was stirred at room temperaturefor 10 min, then2-amino-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one(Intermediate 56) (50 mg, 0.13 mmol) was added and the mixture wasstirred for 2 h. The mixture was purified by flash column chromatographyto give the title compound as a white solid (42 mg, 56% yield).

Step B:(S)—N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)pyrrolidine-3-carboxamide

To a solution of (S)-tert-butyl3-((5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)carbamoyl)pyrrolidine-1-carboxylate(42 mg, 0.072 mmol) in 6 M HCl in MeOH (12 mL) was concentrated todryness to give the title compound as a yellow solid (35 mg, 100%yield), which used in the next step without further purification.

Step C:(S)-1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)pyrrolidine-3-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1. MS (ESI): mass calcd. for C₂₉H₂₅N₅O₄S, 539.6; m/z found,540.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.17-8.07 (m, 1H), 7.44-7.32(m, 2H), 7.28-7.21 (m, 1H), 7.18-7.11 (m, 1H), 7.11-7.00 (m, 3H),6.97-6.89 (m, 1H), 6.68-6.54 (m, 1H), 6.32-6.23 (m, 1H), 5.98-5.88 (m,1H), 5.78-5.68 (m, 1H), 3.99-3.79 (m, 2H), 3.78-3.61 (m, 2H), 3.58-3.49(m, 0.5H), 3.25-3.17 (m, 0.5H), 2.38-2.16 (m, 2H), 2.12 (s, 3H).

Example 545:(R)-1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)pyrrolidine-3-carboxamide

The title compound was prepared using steps A-C in the procedure foundin Example 544, and using(3R)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid in place of(3S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid in step A, toyield the title compound. MS (ESI): mass calcd. for C₂₉H₂₅N₅O₄S, 539.6;m/z found, 540.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.21-8.06 (m, 1H),7.44-7.32 (m, 2H), 7.25 (d, J=8.3 Hz, 1H), 7.20-7.15 (m, 1H), 7.12-7.01(m, 3H), 7.00-6.93 (m, 1H), 6.68-6.54 (m, 1H), 6.34-6.20 (m, 1H),5.97-5.87 (m, 1H), 5.80-5.68 (m, 1H), 3.99-3.80 (m, 2H), 3.79-3.65 (m,2H), 3.59-3.48 (m, 0.5H), 3.27-3.18 (m, 0.5H), 2.37-2.16 (m, 2H), 2.13(s, 3H).

Example 546:(R)—N-(1-(2-(Methylamino)acetyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a microwave vial was added(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860) (150 mg, 0.309 mmol), sarcosine (41.3 mg, 0.463 mmol), THF(4 mL), and HATU (352 mg, 0.927 mmol) and the reaction mixture washeated in microwave at 100° C. for 5 min. The reaction was diluted withDCM, washed with water, and purified by flash column chromatography togive the title compound (125 mg, 72.7% yield). MS (ESI): mass calcd. forC₂₉H₂₈N₆O₄S, 556.6; m/z found, 557.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ8.15 (dd, J=29.9, 5.6 Hz, 1H), 7.48 (s, 1H), 7.34-7.26 (m, 4H),7.24-6.96 (m, 7H), 5.95 (dd, J=22.3, 5.5 Hz, 1H), 5.31 (s, 3H),3.75-3.68 (m, 1H), 3.58-3.45 (m, 2H), 3.44-3.19 (m, 4H), 1.89 (p, J=6.3,5.6 Hz, 2H), 1.81-1.59 (m, 2H).

Example 547:N—((R)-1-((S)-3-Hydroxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) (100 mg, 0.187 mmol), (2S)-3-hydroxy-2-methyl-propanoicacid (35.0 mg, 0.279 mmol), HATU (106 mg, 0.279 mmol), and triethylamine(0.052 mL, 0.37 mmol) in DMF (3 mL) was stirred at rt overnight, thenpurified using flash column chromatography to give the title compound asa yellow solid (40 mg, 100% yield). MS (ESI): mass calcd. forC₃₁H₃₁N₅O₅S, 585.7; m/z found, 586.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.32 (d, J=5.5 Hz, 1H), 7.44-7.36 (m, 2H), 7.33-7.24 (m, 1H), 7.20-7.12(m, 1H), 7.12-7.02 (m, 3H), 7.02-6.93 (m, 1H), 6.07 (d, J=5.5 Hz, 1H),4.39-4.26 (m, 1H), 4.24-3.89 (m, 2H), 3.79-3.66 (m, 1H), 3.58-3.47 (m,1H), 3.17-2.96 (m, 2H), 2.95-2.68 (m, 1H), 2.11 (s, 3H), 2.07-1.99 (m,1H), 1.94-1.78 (m, 1H), 1.75-1.52 (m, 2H), 1.11-0.99 (m, 3H).

Example 548:N-((3S,4S)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using 4-fluoronitrobenzene in place of5-fluoro-2-nitrotoluene in step A, and using tert-butyl(3S,4S)-3-amino-4-methoxy-cyclopentanecarboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G, to yieldthe title compound. MS (ESI): mass calcd. for C₂₉H₂₅N₅O₅S, 555.6; m/zfound, 556.15 [M+H]+. ¹H NMR (600 MHz, CDCl₃): δ 9.67 (s, 1H), 9.60 (s,1H), 8.30 (dd, J=5.5, 1.6 Hz, 1H), 7.97-7.92 (m, 1H), 7.44-7.34 (m, 2H),7.32 (ddt, J=10.1, 7.9, 3.3 Hz, 2H), 7.21-7.07 (m, 5H), 6.41-6.30 (m,2H), 6.10 (dd, J=5.4, 1.1 Hz, 1H), 5.69 (td, J=7.8, 4.8 Hz, 1H), 4.07(d, J=4.3 Hz, 1H), 4.00-3.92 (m, 1H), 3.84-3.70 (m, 2H), 3.67-3.53 (m,1H), 3.49 (d, J=32.6 Hz, 3H).

Example 549:(R,Z)—N-(1-(4-Amino-2-fluorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R,Z)-tert-butyl(3-fluoro-4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate

A solution of (E)-4-(tert-butoxycarbonylamino)-2-fluoro-but-2-enoic acid(Intermediate 52) (105 mg, 0.480 mmol), HATU (182 mg, 0.480 mmol), andtriethylamine (202 mg, 2.00 mmol) in anhydrous DMF (5 mL) was stirred atroom temperature for 10 min, then(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) (200 mg, 0.40 mmol) was added and the mixture was stirredfor 2 hr. The reaction mixture was purified by flash columnchromatography to give the title compound as a light yellow solid (124mg, 24.0% yield).

Step B:(R,Z)—N-(1-(4-Amino-2-fluorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R,Z)-tert-butyl(3-fluoro-4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate(124 mg, 0.0973 mmol) in 6 M HCl in MeOH (10 mL) was concentrated todryness at 50° C., and was purified by flash column chromatography togive the title compound as a light yellow solid (25 mg, 98% yield). MS(ESI): mass calcd. for C₃₁H₂₉FN₆O₄S, 600.7; m/z found, 601.4 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.32-8.19 (m, 1H), 7.42-7.33 (m, 2H), 7.30-7.21(m, 1H), 7.18-7.12 (m, 1H), 7.11-7.01 (m, 3H), 6.99-6.90 (m, 1H),6.07-5.93 (m, 1H), 5.80-5.64 (m, 1H), 4.35-3.88 (m, 3H), 3.65-3.40 (m,2H), 3.27-2.94 (m, 2H), 2.11 (s, 3H), 2.07-1.86 (m, 2H), 1.85-1.69 (m,1H), 1.67-1.52 (m, 1H).

Example 550:(R,Z)—N-(1-(4-Amino-2-chlorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using a method analogous to Example 75using(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) and using(Z)-4-(tert-butoxycarbonylamino)-2-chloro-but-2-enoic acid (Intermediate53). MS (ESI): mass calcd. for C₃₁H₂₉ClN₆O₄S, 617.1; m/z found, 617.4[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.40-8.29 (m, 2H), 7.44-7.36 (m, 2H),7.32-7.26 (m, 1H), 7.22-7.14 (m, 1H), 7.12-7.03 (m, 3H), 7.01-6.95 (m,1H), 6.36-6.15 (m, 1H), 6.12-6.05 (m, 1H), 4.31-3.70 (m, 5H), 3.09-2.78(m, 2H), 2.19-2.04 (m, 4H), 1.97-1.86 (m, 1H), 1.85-1.73 (m, 1H),1.72-1.57 (m, 1H).

Example 551:(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(1,1(R)-5-([1,1′-Biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps C-H, in Example 1, and using [1,1′-biphenyl]-3-amine(Intermediate 46) in place of 2-methyl-4-phenoxyaniline in step C, andusing (R)-tert-butyl 3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₆H₂₃N₅O₂S,469.56; m/z found, 470.3 [M+H]⁺.

Step B: (R)-tert-Butyl(2-(3-(5-([1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-2-oxoethyl)(methyl)carbamate

To a solution of 2-[tert-butoxycarbonyl(methyl)amino]acetic acid(Intermediate 21) (0.189 g, 1.00 mmol), HATU (0.38 g, 1.0 mmol), andtriethylamine (0.202 g, 2.00 mmol) in DMF (5 mL) was added(R)-5-([1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(0.47 g, 1.0 mmol) and was stirred at room temperature for 30 minutes.The reaction was purified by normal phase flash column chromatography(SiO₂) to give the title compound (0.577 g, 90.0% yield).

Step C:(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (R)-tert-butyl(2-(3-(5-([1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-2-oxoethyl)(methyl)carbamate(0.256 g, 0.400 mmol) in MeOH (15 mL) was added saturated aqueous HCl(1.5 mL). The mixture was concentrated to dryness and the residue wasdispersed between DCM and 10% aqueous NH₃. The organic layer wascollected and purified by preparative TLC to give the title compound (86mg, 39% yield). MS (ESI): mass calcd. for C₂₉H₂₈N₆O₃S, 540.6; m/z found,541.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.95-8.60 (br, 1H), 8.36-8.27(m, 1H), 8.27-8.10 (m, 1H), 7.88-7.79 (m, 1H), 7.79-7.73 (m, 1H),7.70-7.62 (m, 3H), 7.48-7.34 (m, 4H), 6.11-6.02 (m, 1H), 4.46-3.94 (m,3H), 3.92-3.73 (m, 1H), 3.72-3.50 (m, 1H), 3.20-2.92 (m, 2H), 2.87-2.63(m, 1H), 2.53 (s, 3H), 1.97-1.87 (m, 1H), 1.80-1.60 (m, 2H), 1.55-1.35(m, 1H).

Example 552:(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-([1,1′-Biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps C-H, in Example 1, and using [1,1′-biphenyl]-3-amine(Intermediate 46) in place of 2-methyl-4-phenoxyaniline in step C, andusing (R)-tert-butyl 3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₆H₂₃N₅O₂S,469.56; m/z found, 470.3 [M+H]⁺.

Step B:(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-([1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(188 mg, 0.400 mmol) in DCM (10 mL) were added formaldehyde (2 mL, 37wt. % in H₂O) and NaBH(OAc)₃ (339 mg, 1.60 mmol) and was stirred at roomtemperature for 4 hours. To the mixture were added DCM (50 mL), MeOH (5mL), and water (30 mL). The organic layer was collected, concentrated todryness, and purified by TLC (MeOH/DCM=1/20) to give the title compound(69 mg, 35% yield) as a yellow solid. MS (ESI): mass calcd. forC₂₇H₂₅N₅O₂S, 483.6; m/z found, 484.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 8.29-8.23 (m, 1H), 8.08-7.98 (m, 1H), 7.84-7.79 (m, 1H), 7.77-7.73 (m,1H), 7.70-7.63 (m, 3H), 7.49-7.43 (m, 2H), 7.43-7.34 (m, 2H), 6.07-5.99(m, 1H), 3.97-3.89 (m, 1H), 3.43 (br, 1H), 2.86-2.80 (m, 1H), 2.70-2.63(m, 1H), 2.20 (s, 3H), 1.99-1.85 (m, 2H), 1.80-1.73 (m, 1H), 1.72-1.64(m, 1H), 1.56-1.45 (m, 1H), 1.39-1.28 (m, 1H).

Example 553:(R)-5-(3′-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(Example 540, Step A) (400 mg, 0.70 mmol), m-tolylboronic acid (105 mg,0.770 mmol), Pd(dppf)Cl₂ (29 mg, 0.035 mmol), and Na₂CO₃ (148 mg, 1.40mmol) in dioxane (10 mL) and H₂O (1 mL) was stirred at 110° C. for 2 h.The reaction mixture was concentrated to dryness and the residue waspurified by flash column chromatography. The solid was dissolved in MeOH(4 mL) and saturated aqueous HCl (4 mL), and the mixture was heated to50° C. and stirred for 30 min. The reaction mixture was concentrated todryness and the residue was purified by flash column chromatography togive the title compound (280 mg, 80% yield). MS (ESI): mass calcd. forC₂₇H₂₅N₅O₂S, 483.6; m/z found, 484.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.21 (d, J=5.6 Hz, 1H), 7.79-7.74 (m, 1H), 7.68-7.61 (m, 2H), 7.48-7.45(m, 1H), 7.44-7.41 (m, 1H), 7.37-7.28 (m, 2H), 7.19-7.14 (m, 1H), 6.10(d, J=5.6 Hz, 1H), 4.19-4.10 (m, 1H), 3.28-3.25 (m, 1H), 3.13-3.03 (m,1H), 2.85-2.73 (m, 2H), 2.38 (s, 3H), 2.06-1.97 (m, 1H), 1.97-1.87 (m,1H), 1.75-1.66 (m, 2H).

Example 554:(R)-5-(2′-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using using the procedure found inExample 553, step B, and using o-tolylboronic acid in place ofm-tolylboronic acid, to yield the title compound. MS (ESI): mass calcd.for C₂₇H₂₅N₅O₂S, 483.6; m/z found, 484.3 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.21 (d, J=5.6 Hz, 1H), 7.68-7.61 (m, 1H), 7.52-7.43 (m, 1H),7.43-7.30 (m, 2H), 7.29-7.19 (m, 4H), 6.10 (d, J=5.6 Hz, 1H), 4.16-4.04(m, 1H), 3.27-3.21 (m, 1H), 3.08-3.00 (m, 1H), 2.83-2.69 (m, 2H), 2.29(s, 3H), 2.06-1.98 (m, 1H), 1.95-1.85 (m, 1H), 1.75-1.63 (m, 2H).

Example 555:5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((E)-4-((4aR,7aS)-tetrahydro-2H-[1.4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoyl)pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using a method analogous to Example 75using(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 36) and(E)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoicacid (Intermediate 72). MS (ESI): mass calcd. for C₃₆H₃₆N₆O₆S, 680.8;m/z found, 681.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35-8.27 (m, 1H),7.45-7.26 (m, 3H), 7.20-6.93 (m, 5H), 6.87-6.73 (m, 1H), 6.62-6.45 (m,1H), 6.11-6.01 (m, 1H), 4.68-4.55 (m, 1H), 4.20-4.07 (m, 2H), 4.00-3.71(m, 4H), 3.62-3.41 (m, 6H), 3.14-3.01 (m, 2H), 3.01-2.88 (m, 2H),2.39-2.01 (m, 5H).

Example 556:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2-phenoxypyrimidin-5-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 2-chloro-5-nitro-pyrimidine in place of5-fluoro-2-nitrotoluene in step A, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in stepG, to yield the title compound. MS (ESI): mass calcd. for C₂₇H₂₃N₇O₄S,541.6; m/z found, 542.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.71 (s, 2H),8.36-8.31 (m, 1H), 7.49-7.39 (m, 2H), 7.31-7.20 (m, 3H), 6.83-6.68 (m,1H), 6.38-6.32 (m, 1H), 6.22-6.12 (m, 1H), 5.77-5.64 (m, 1H), 4.35-3.86(m, 3H), 3.18-3.12 (m, 1H), 2.96-2.80 (m, 1H), 2.11-1.99 (m, 1H),1.90-1.80 (m, 1H), 1.79-1.64 (m, 1H), 1.62-1.48 (m, 1H).

Example 557:N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared as in Example 33, steps A-D, and using(3R,5S)-tert-butyl 3-amino-5-hydroxypiperidine-1-carboxylate in placetert-butyl (3R)-3-aminopiperidine-1-carboxylate in step D. MS (ESI):mass calcd. for C₂₇H₂₉N₅O₅S, 535.6; m/z found, 536.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.37 (d, J=5.9 Hz, 1H), 7.27-7.14 (m, 1H), 7.03-6.95 (m,1H), 6.94-6.87 (m, 1H), 6.84-6.69 (m, 1H), 6.28-6.01 (m, 2H), 5.78-5.62(m, 1H), 4.71-4.62 (m, 1H), 4.60-3.81 (m, 4H), 3.25-3.15 (m, 1H),3.02-2.94 (m, 1H), 2.19-1.83 (m, 5H), 1.39-1.29 (m, 6H).

Example 558:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(3-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5, 8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using 2-chloro-1-fluoro-4-nitro-benzene in placeof 5-fluoro-2-nitrotoluene in step A, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G, to yieldthe title compound. MS (ESI): mass calcd. for C₂₈H₂₂ClN₅O₄S, 560.0; m/zfound, 560.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35-8.30 (m, 1H),7.69-7.65 (m, 1H), 7.44-7.32 (m, 3H), 7.20-7.11 (m, 2H), 7.09-7.02 (m,2H), 6.67-6.52 (m, 1H), 6.31-6.24 (m, 1H), 6.24-6.20 (m, 1H), 5.78-5.69(m, 1H), 4.66-4.55 (m, 1H), 4.02-3.47 (m, 4H), 2.38-2.20 (m, 1H),2.19-2.01 (m, 1H).

Example 559:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5, 8-triazaacenaphthylene-2-carboxamide

Step A: 2-Phenylpyridin-4-amine

To a stirred solution of 2-chloropyridin-4-amine (64.0 g, 498 mmol) intoluene (800 mL) were added phenylboronic acid (72.9 g, 597 mmol),Pd(PPh₃)₄ (28.8 g, 24.9 mmol), Na₂CO₃ (105.5 g, 995.6 mmol), and water(500 mL) and was heated at 100° C. for 16 hours. The reaction was cooledto room temperature, extracted three times with ethyl acetate, and thecombined organic phases were concentrated to dryness. The residue waspurified by normal phase flash column chromatography (SiO₂) to give thetitle compound (60 g, 71% yield) as a white solid.

Step B:(R)-4-oxo-5-(2-phenylpyridin-4-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-F in Example 1, and using 2-phenylpyridin-4-amine in place of2-methyl-4-phenoxy-aniline in step C and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G.

Step C:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Example 75(R)-4-oxo-5-(2-phenylpyridin-4-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamideand using (E)-2-cyano-3-cyclopropylacrylic acid (Intermediate 17) inplace of 3-hydroxypropanoic acid. MS (ESI): mass calcd. for C₃₂H₂₇N₇O₃S,589.7; m/z found, 590.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.88-8.84 (m,1H), 8.36-8.31 (m, 1H), 8.06-8.00 (m, 3H), 7.53-7.41 (m, 4H), 6.58-6.50(m, 1H), 6.35-6.29 (m, 1H), 4.23-3.89 (m, 3H), 3.22-2.91 (m, 2H),2.12-1.96 (m, 2H), 1.93-1.82 (m, 1H), 1.77-1.56 (m, 2H), 1.25-1.15 (m,2H), 1.03-0.92 (m, 1H), 0.92-0.80 (m, 1H).

Example 560:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(cyclohexyloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using cyclohexyl methanesulfonate and3-nitrophenol in place of 5-fluoro-2-nitrotoluene and phenol in step A,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G,to yield the title compound. MS (ESI): mass calcd. for C₂₉H₃₁N₅O₄S,545.7; m/z found, 546.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.26 (d,J=5.6 Hz, 1H), 7.50-7.38 (m, 1H), 7.11-6.99 (m, 2H), 6.99-6.92 (m, 1H),6.84-6.71 (m, 1H), 6.25-6.15 (m, 1H), 6.11 (d, J=5.6 Hz, 1H), 5.77-5.64(m, 1H), 4.54-4.28 (m, 2H), 4.23-3.89 (m, 2H), 3.20-3.08 (m, 1H),2.92-2.81 (m, 1H), 2.10-1.94 (m, 3H), 1.89-1.67 (m, 4H), 1.61-1.47 (m,4H), 1.43-1.26 (m, 3H).

Example 561:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(cyclopentyloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared analogous to Example 33, steps A-D, andusing 3-nitrophenol and 2-iodopropane in place of 3-methyl-4-nitrophenoland 5-fluoro-2-nitrotoluene in Step A. MS (ESI): mass calcd. forC₂₈H₂₉N₅O₄S, 531.6; m/z found, 532.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD andDMSO-d₆): δ 8.44-8.33 (m, 1H), 7.58-7.48 (m, 1H), 7.16-7.08 (m, 1H),7.07-6.97 (m, 2H), 6.90-6.78 (m, 1H), 6.27-6.15 (m, 2H), 5.84-5.72 (m,1H), 4.94-4.84 (m, 1H), 4.38-3.93 (m, 3H), 3.26-3.06 (m, 1H), 2.97-2.78(m, 1H), 2.14-1.91 (m, 4H), 1.90-1.75 (m, 6H), 1.71-1.64 (m, 2H).

Example 562:(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-Isopropoxy-2-methylphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared analagous to Example 33, steps A-D inusing (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate.

Step B:(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using a method analogous to Example 75with(R)-5-(4-Isopropoxy-2-methylphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamideand (E)-4-(dimethylamino)but-2-enoic acid. MS (ESI): mass calcd. forC₂₉H₃₄N₆O₄S, 562.7; m/z found, 563.5 [M+H]⁺. ¹H NMR (400 MHz, CD3OD): δ8.42 (s, 1H), 8.33-8.23 (m, 1H), 7.29-7.13 (m, 1H), 7.01-6.86 (m, 2H),6.83-6.58 (m, 2H), 6.08-5.97 (m, 1H), 4.72-4.53 (m, 2H), 4.09-3.44 (m,6H), 2.80-2.66 (m, 6H), 2.42-2.20 (m, 1H), 2.16-2.04 (m, 4H), 1.41-1.24(m, 6H).

Example 563:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a stirred solution of5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 57) (3.5 g, 9.0 mmol) in DMF (15 mL) were addedtert-butyl (3R)-3-aminopiperidine-1-carboxylate (3.6 g, 18 mmol), HATU(5.1 g, 13 mmol), and diisopropylethylamine (2.3 g, 18 mmol) and wasstirred at room temperature overnight. The solvent was removed and theresidue was partitioned between ethyl acetate and water. The organiclayer was separated, shaken with brine and dried over anhydrous Na₂SO₄.The residue was purified by flash column chromatography to give thetitle compound as yellow solid (3.0 g, 58% yield).

Step B: (R)-tert-Butyl3-(4-oxo-5-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

A solution of (R)-tert-butyl3-(5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(180 mg, 0.314 mmol), [2-(trifluoromethyl)phenyl]boronic acid (90.0 mg,0.474 mmol), Pd(dppf)Cl₂*CH₂Cl₂ (30.0 mg, 0.0367 mmol), and Na₂CO₃ (85mg, 0.80 mmol) in dioxane (7 mL) and H₂O (1 mL) was sparged with N₂ andstirred at 120° C. for 4 h. The reaction was cooled and purified byflash column chromatography to give the title compound as yellow solid(150 mg, 75% yield).

Step C:(R)-4-Oxo-N-(piperidin-3-yl)-5-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(4-oxo-5-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(150 mg, 0.235 mmol) in saturated aqueous HCl (2 mL) and MeOH (15 mL)was stirred at room temperature for about 2 hours. The reaction mixturewas concentrated to dryness to give the title compound (110 mg, 87%yield), which was carrying forward to next step without purification.

Step D:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, to yield the title compound (67 mg, 55% yield). MS(ESI): mass calcd. for C₃₀H₂₄F₃N₅O₃S, 591.6; m/z found, 592.4 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 10.11 (s, 1H), 8.33 (d, J=5.5 Hz, 1H),8.13-7.99 (m, 1H), 785-7.79 (m, 1H), 7.77-7.69 (m, 1H), 7.68-7.58 (m,2H), 7.54-7.34 (m, 4H), 6.86-6.65 (m, 1H), 6.13-6.01 (m, 1H), 5.97 (d,J=5.5 Hz, 1H), 5.70-5.58 (m, 1H), 4.51-4.10 (m, 1H), 4.06-3.88 (m, 1H),3.84-3.69 (m, 1H), 3.15-2.89 (m, 1H), 2.81-2.56 (m, 1H), 2.00-1.85 (m,1H), 1.82-1.71 (m, 1H), 1.68-1.54 (m, 1H), 1.48-1.31 (m, 1H).

Example 564:N—((R)-1-((R)-3-Hydroxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (R)-3-hydroxy-2-methylpropanoic acid (35 mg, 0.28mmol), HATU (106 mg, 0.279 mmol), and triethylamine (0.0521 mL, 0.347mmol) in DMF (3 mL) was added(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) (100 mg, 0.22 mmol) and was stirred at room temperatureovernight. The mixture was purified by normal phase flash columnchromatography (SiO₂) to give the title compound (20 mg, 100% yield). MS(ESI): mass calcd. for C₃₁H₃₁N₅O₅S, 585.7; m/z found, 586.2 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.32 (d, J=5.1 Hz, 1H), 7.44-7.34 (m, 2H),7.33-7.25 (m, 1H), 7.20-7.13 (m, 1H), 7.12-7.02 (m, 3H), 7.01-6.92 (m,1H), 6.06 (d, J=5.4 Hz, 1H), 4.54-4.17 (m, 2H), 4.01-3.91 (m, 1H),3.78-3.66 (m, 1H), 3.55-3.45 (m, 1H), 3.19-3.02 (m, 2H), 2.91-2.78 (m,1H), 2.11 (s, 3H), 2.07-1.99 (m, 1H), 1.86-1.66 (m, 2H), 1.62-1.45 (m,1H), 1.16-1.02 (m, 3H).

Example 565:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-C, and using 3-isopropoxyaniline in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₂₆H₂₇N₅O₄S,505.6; m/z found, 506.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): δ 10.23-10.06(d, J=15.2 Hz, 1H), 8.39-8.27 (d, J=5.5 Hz, 1H), 8.12-8.00 (m, 1H),7.54-7.43 (m, 1H), 7.10-7.02 (m, 2H), 7.01-6.94 (m, 1H), 6.87-6.72 (m,1H), 6.15-6.07 (d, J=16.6 Hz, 1H), 6.06-6.00 (d, J=5.5 Hz, 1H),5.74-5.65 (d, J=10.4 Hz, 1H), 4.67-4.56 (m, 1H), 4.53-4.16 (m, 1H),4.11-3.93 (m, 1H), 3.85-3.73 (m, 1H), 3.16-2.94 (m, 1H), 2.80-2.63 (m,1H), 1.99-1.90 (m, 1H), 1.82-1.75 (m, 1H), 1.74-1.60 (m, 1H), 1.49-1.36(m, 1H), 1.31-1.26 (m, 6H).

Example 566:(R)-5-(3-Acetylphenyl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-C, and using 1-(3-aminophenyl)ethanone in place of3-cyclobutylaniline in step A, to yield the title compound. MS (ESI):mass calcd. for C₂₅H₂₃N₅O₄S, 489.6; m/z found, 490.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆): δ 10.31-10.12 (m, 1H), 8.38-8.27 (d, J=5.5 Hz, 1H),8.17-8.04 (m, 3H), 7.82-7.72 (m, 2H), 6.89-6.71 (m, 1H), 6.18-6.08 (d,J=16.7 Hz, 1H), 6.06-5.98 (d, J=5.5 Hz, 1H), 5.72-5.64 (d, J=10.4 Hz,1H), 4.54-4.16 (m, 1H), 4.11-3.95 (m, 1H), 3.87-3.74 (m, 1H), 3.16-2.94(m, 1H), 2.82-2.64 (m, 1H), 2.64-2.57 (s, 3H), 1.99-1.91 (m, 1H),1.83-1.58 (m, 2H), 1.51-1.37 (m, 1H).

Example 567:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 2-phenylpyridin-4-amine in place of2-methyl-4-phenoxy-aniline in step C, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G, to yieldthe title compound. MS (ESI): mass calcd. for C₂₇H₂₂N₆O₃S, 510.6; m/zfound, 511.1 [M+H]+. ¹H NMR (400 MHz, CD₃OD): δ 8.87-8.80 (m, 1H),8.28-8.22 (m, 1H), 8.05-7.98 (m, 3H), 7.51-7.41 (m, 4H), 6.66-6.52 (m,1H), 6.30-6.22 (dd, J=16.4, 2.9 Hz, 2H), 5.76-5.70 (m, 1H), 4.67-4.56(m, 1H), 4.02-3.48 (m, 4H), 2.38-2.21 (m, 1H), 2.20-2.03 (m, 1H).

Example 568:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsB-I in Example 1, and using 1-nitro-3-(trifluoromethoxy)benzene in placeof 2-methyl-1-nitro-4-phenoxy-benzene in step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₄H₂₀F₃N₅O₄S, 531.5; m/z found, 532.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.30 (d, J=5.5 Hz, 1H), 7.77-7.64 (m, 1H), 7.55-7.44(m, 3H), 6.87-6.70 (m, 1H), 6.24-6.14 (m, 1H), 6.13-6.06 (m, 1H),5.78-5.64 (m, 1H), 4.56-4.25 (m, 1H), 4.21-3.86 (m, 2H), 3.22-3.10 (m,1H), 2.97-2.81 (m, 1H), 2.12-1.94 (m, 1H), 1.92-1.80 (m, 1H), 1.79-1.64(m, 1H), 1.62-1.50 (m, 1H).

Example 569:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclopropylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 3-cyclopropylaniline in place of2-methyl-4-phenoxy-aniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₆H₂₅N₅O₃S, 487.6; m/z found, 488.9 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.31-8.22 (m, 1H), 7.51-7.41 (m, 1H), 7.28-7.22 (m, 1H),7.20-7.11 (m, 2H), 6.84-6.72 (m, 1H), 6.25-6.13 (m, 1H), 6.11-6.03 (m,1H), 5.78-5.67 (m, 1H), 4.56-4.26 (m, 1H), 4.21-3.90 (m, 2H), 3.21-3.10(m, 1H), 2.97-2.81 (m, 1H), 2.10-2.03 (m, 1H), 2.02-1.93 (m, 1H),1.91-1.82 (m, 1H), 1.79-1.65 (m, 1H), 1.63-1.52 (s, 1H), 1.05-0.97 (m,2H), 0.79-0.70 (m, 2H)

(R,E)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-([11′-Biphenyl]-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using [1,1′-biphenyl]-3-amine (Intermediate 46) inplace of 2-methyl-4-phenoxy-aniline in step C, and using (R)-tert-butyl3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₅H₂₁N₅O₂S, 455.53; m/z found, 456.3 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.29 (d, J=5.6 Hz, 1H), 7.85-7.77 (m, 1H), 7.76-7.59(m, 4H), 7.49-7.39 (m, 3H), 7.39-7.30 (m, 1H), 6.18 (d, J=5.6 Hz, 1H),4.63-4.5.3 (m, 1H), 3.65-3.51 (m, 2H), 3.47-3.34 (m, 2H), 2.48-2.31 (m,1H), 2.27-2.13 (m, 1H).

Step B:(R,E)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (E)-4-(dimethylamino)but-2-enoic acid (34 mg, 0.26 mmol),HATU (100 mg, 0.264 mmol), and triethylamine (111 mg, 1.11 mmol) in DMF(5 mL) was stirred at room temperature for 10 minutes, then(R)-5-([1,1′-biphenyl]-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.22 mmol) was added and was stirred at room temperature for 2h. The mixture was purified by normal phase flash column chromatography(SiO₂) to give the title compound (78 mg, 99% yield). MS (ESI): masscalcd. for C₃₁H₃₀N₆O₃S, 566.7; m/z found, 567.5 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.47 (s, 1H), 8.28-8.22 (m, 1H), 7.83-7.76 (m, 1H), 7.75-7.70(m, 1H), 7.68-7.61 (m, 3H), 7.46-7.37 (m, 3H), 7.36-7.28 (m, 1H),6.85-6.69 (m, 1H), 6.58-6.41 (m, 1H), 6.18-6.10 (m, 1H), 4.67-4.51 (m,1H), 4.00-3.45 (m, 4H), 3.41-3.32 (m, 2H), 2.44 (s, 3H), 2.42 (s, 3H),2.35-2.18 (m, 1H), 2.15-2.00 (m, 1H).

Example 571:N—((R)-1-((R)-3-Methoxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsG, in Example 1, and using(2R)-1-[(3R)-3-amino-1-piperidyl]-3-methoxy-2-methyl-propan-1-one(Intermediate 50) in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G, to yieldthe title compound as a yellow solid (70 mg, 100% yield). MS (ESI): masscalcd. for C₃₂H₃₃N₅O₅S, 599.7; m/z found, 600.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆ and CD₃OD): δ 8.27 (d, J=5.5 Hz, 1H), 7.40-7.30 (m, 2H),7.29-7.21 (m, 1H), 7.15-7.07 (m, 1H), 7.07-6.98 (m, 3H), 6.94-6.87 (m,1H), 5.97 (d, J=5.5 Hz, 1H), 4.10-4.02 (m, 1H), 3.96-3.71 (m, 2H),3.50-3.41 (m, 1H), 3.26-3.18 (m, 3H), 3.16-3.12 (m, 1H), 3.11-2.95 (m,2H), 2.73-2.62 (m, 1H), 2.04 (s, 3H), 1.98-1.91 (m, 1H), 1.78-1.70 (m,1H), 1.67-1.55 (m, 1H), 1.51-1.35 (m, 1H), 1.06-0.91 (m, 3H)

Example 572:(R)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(2-(dimethylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using a method analogous to Example 75using(R)-5-(3-chloro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 581) and using 2-(dimethylamino)acetic acid in place of3-hydroxypropanoic acid. MS (ESI): mass calcd. for C₃₀H₂₉ClN₆O₄S, 605.1;m/z found, 606.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.40 (s, 1H),8.36-8.28 (m, 1H), 7.70-7.64 (m, 1H), 7.45-7.32 (m, 3H), 7.23-7.11 (m,2H), 7.10-7.02 (m, 2H), 6.27-6.16 (m, 1H), 4.56-4.30 (m, 1H), 4.25-4.06(m, 2H), 4.03-3.56 (m, 2H), 3.15-2.97 (m, 1H), 2.91-2.75 (m, 7H),2.11-1.49 (m, 4H).

Example 573:(R,E)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-([1,1′-Biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-G in Example 1, and using [1,1′-biphenyl]-3-amine (Intermediate 46) inplace of 2-methyl-4-phenoxy-aniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₆H₂₃N₅O₂S, 469.56; m/z found, 470.3 [M+H]⁺.

Step B:(R,E)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (E)-4-(dimethylamino)but-2-enoic acid (52 mg, 0.40mmol), HATU (152 mg, 0.400 mmol), and triethylamine (81 mg, 0.80 mmol)in DMF (3 mL) was added(R)-5-([1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(188 mg, 0.400 mmol) and was stirred at room temperature for 30 minutes.The mixture was purified by normal phase flash column chromatography(SiO₂) to give the title compound (101 mg, 42.0% yield). MS (ESI): masscalcd. for C₃₂H₃₂N₆O₃S, 580.7; m/z found, 581.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 8.36-8.08 (m, 3H), 7.82-7.77 (m, 1H), 7.74-7.70 (m, 1H),7.69-7.66 (m, 2H), 7.65-7.61 (m, 1H), 7.48-7.43 (m, 2H), 7.39-7.34 (m,2H), 6.59-6.51 (m, 2H), 6.03-5.96 (m, 1H), 4.46-3.68 (m, 3H), 3.04-2.99(m, 2H), 2.96-2.81 (m, 1H), 2.80-2.52 (m, 1H), 2.12 (s, 6H), 1.95-1.88(m, 1H), 1.80-1.71 (m, 1H), 1.68-1.53 (m, 1H), 1.47-1.34 (m, 1H).

Example 1:N-(cis)-1-Acryloyl-3-hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Method 1,step I in Example 1, and usingN-(cis-3-hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 659). MS (ESI): mass calcd. for C₂₉H₂₅N₅O₅S, 555.6; m/z found,556.9 [M+H]+. ¹H NMR (400 MHz, CD₃OD): δ 8.34 (d, J=5.6 Hz, 1H), 8.03(s, 1H), 7.57 (s, 1H), 7.47-7.37 (m, 1H), 7.32 (d, J=8.5 Hz, 1H),7.25-7.08 (m, 4H), 6.71 (dd, J=16.9, 10.6 Hz, 1H), 6.32-6.17 (m, 2H),6.00 (s, 1H), 5.81-5.67 (m, 2H), 5.38 (s, 1H), 4.74-4.63 (m, 2H),4.28-3.99 (m, 4H), 3.58 (s, 1H), 2.08-1.79 (m, 2H).

Example 575:(R)-5-(3-Chloro-4-phenoxyphenl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of 2-((tert-butoxycarbonyl)(methyl)amino)acetic acid (61 mg,0.32 mmol), HATU (123 mg, 0.323 mmol), and triethylamine (136 mg, 1.35mmol) in DMF (3 mL) was stirred at room temperature for 10 minutes. Then(R)-5-(3-chloro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 581) (150 mg, 0.27 mmol) was added and was stirred for 2 h. Themixture was purified by normal phase flash column chromatography (SiO₂)to give a white solid. The solid was dissolved in 6 M HCl/MeOH and thenconcentrated to dryness. The residue was purified by normal phase flashcolumn chromatography (SiO₂) to give the title compound (101 mg, 99.4%yield) as a light yellow solid. MS (ESI): mass calcd. for C₂₉H₂₇ClN₆O₄S,591.1; m/z found, 591.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.42 (s, 1H),8.36-8.27 (m, 1H), 7.70-7.60 (m, 1H), 7.46-7.28 (m, 3H), 7.21-7.11 (m,2H), 7.09-7.00 (m, 2H), 6.25-6.15 (m, 1H), 4.52-4.21 (m, 1H), 4.18-4.03(m, 2H), 4.02-3.90 (m, 1H), 3.89-3.56 (m, 1H), 3.17-3.01 (m, 1H),2.96-2.83 (m, 1H), 2.73 (s, 3H), 2.10-1.96 (m, 1H), 1.95-1.50 (m, 3H).

Example 576:(R)—N-(1-(2-Methoxyacetyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

In a microwave vial were added(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860) (200 mg, 0.412 mmol), methoxyacetic acid (57 mg, 0.62mmol), THF (10 mL), and HATU (470 mg, 1.24 mmol). The reaction washeated in microwave at 100° C. for 5 minutes. The reaction was dilutedwith DCM and washed with water. The reaction was purified by normalphase flash column chromatography (SiO₂) to give the title compound (210mg, 91% yield). MS (ESI): mass calcd. for C₂₉H₂₇N₅O₅S, 557.6; m/z found,557.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.53 (s, 1H), 8.28 (d, J=5.6Hz, 1H), 8.21 (d, J=5.7 Hz, 1H), 7.37 (q, J=7.0, 6.4 Hz, 3H), 7.29 (s,2H), 7.21-7.02 (m, 3H), 6.05 (dd, J=24.2, 5.5 Hz, 2H), 4.26 (s, 2H),3.66-3.51 (m, 5H), 3.30 (s, 3H), 1.97-1.54 (m, 4H).

Example 577:(R)-5-(3-Chloro-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 2-chloro-1-fluoro-4-nitro-benzene in placeof 5-fluoro-2-nitrotoluene in step A, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₅H₂₀ClN₅O₃S, 506.0; m/z found, 506.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.18-8.13 (m, 1H), 7.57-7.52 (m, 1H), 7.42-7.36 (m,2H), 7.30-7.25 (m, 1H), 7.18-7.12 (m, 2H), 7.08-7.03 (m, 2H), 6.07-6.03(m, 1H), 4.63-4.56 (m, 1H), 3.44-3.36 (m, 1H), 3.35-3.31 (m, 1H),3.27-3.22 (m, 1H), 3.22-3.15 (m, 1H), 2.35-2.24 (m, 1H), 2.14-2.06 (m,1H).

Example 578:4-Oxo-N-(6-oxopiperidin-3-yl)-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G in Example 1, and using 4-fluoronitrobenzene in place of5-fluoro-2-nitrotoluene in step A, and using 5-amino-piperidin-2-onehydrochloride in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₆H₂₁N₅O₄S, 499.5; m/z found, 500.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): δ 8.41-8.30 (m, 1H), 7.49-7.09 (m, 10H), 6.26-6.15 (m, 1H),4.40 (dd, J=12.8, 7.2 Hz, 1H), 3.73-3.70 (m, 3H), 3.60 (dd, J=12.6, 5.7Hz, 1H), 3.44-3.35 (m, 1H), 3.33-3.25 (m, 1H), 2.58-2.47 (m, 2H).

Example 579:N-((3S,4S)-4-Fluoropyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example506, steps A-B, and using 4-phenoxyaniline and (3S,4S)-tert-butyl3-amino-4-fluoropyrrolidine-1-carboxylate to give an off white solid. MS(ESI): mass calcd. for C₂₅H₂₀FN₅O₃S, 489.5; m/z found, 490.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): δ 8.34-8.29 (m, 1H), 7.45-7.35 (m, 2H), 7.33-7.25(m, 2H), 7.23-7.08 (m, 5H), 6.18-6.12 (m, 1H), 4.56 (ddd, J=18.7, 6.9,3.4 Hz, 1H), 3.48 (ddd, J=9.8, 6.8, 2.6 Hz, 1H), 3.28-3.08 (m, 6H), 2.89(dt, J=12.0, 3.4 Hz, 1H).

Example 580:(R)-5-(4′-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example498, steps A-C, and using p-tolylboronic acid in place of(2,3-difluorophenyl)boronic acid in step B. MS (ESI): mass calcd. forC₂₇H₂₅N₅O₂S, 483.6; m/z found, 484.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.52 (s, 1H), 8.26 (d, J=5.6 Hz, 1H), 7.83-7.72 (m, 1H), 7.69-7.60 (m,2H), 7.58-7.49 (m, 2H), 7.39-7.31 (m, 1H), 7.28-7.20 (m, 2H), 6.14 (d,J=5.6 Hz, 1H), 4.28-4.15 (m, 1H), 3.53-3.40 (m, 1H), 3.27-3.16 (m, 1H),2.97-2.83 (m, 2H), 2.34 (s, 3H), 2.12-1.95 (m, 2H), 1.90-1.65 (m, 2H).

Example 581:(R)-5-(3-Chloro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedure using Method 1,steps A-H in Example 1, using 3-chloro-4-fluoronitroaniline in step Aand tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G.MS (ESI): mass calcd. for C₂₆H₂₂ClN₅O₃S, 520.0; m/z found, 520.9 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ 8.11-8.01 (m, 1H), 7.53-7.46 (m, 1H),7.43-7.32 (m, 2H), 7.30-7.20 (m, 1H), 7.20-7.09 (m, 2H), 7.09-7.00 (m,2H), 6.02-5.91 (m, 1H), 4.03-3.87 (m, 1H), 3.21-3.08 (m, 1H), 2.95-2.80(m, 1H), 2.68-2.52 (m, 2H), 2.06-2.00 (m, 1H), 1.87-1.75 (m, 1H),1.70-1.48 (m, 2H).

Example 582:(R)—N-(1-Acetylpiperidin-3-yl)-5-(3-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(3-chloro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 581) (150 mg, 0.288 mmol) and a catalytic amount of DMAP in DCM(25 mL) was added acetic anhydride (35 mg, 0.35 mmol) and was stirred atrt for 20 min. The reaction mixture was concentrated to dryness and theresidue was purified by flash column chromatography to give the titlecompound as a light yellow solid (96 mg, 59% yield). MS (ESI): masscalcd. for C₂₈H₂₄ClN₅O₄S, 562.0; m/z found, 562.5 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.36-8.26 (m, 1H), 7.75-7.64 (m, 1H), 7.46-7.30 (m, 3H),7.22-7.10 (m, 2H), 7.09-7.00 (m, 2H), 6.21 (d, J=5.6 Hz, 1H), 4.55-4.20(m, 1H), 4.08-3.68 (m, 2H), 3.14-2.98 (m, 1H), 2.82-2.65 (m, 1H), 2.12(d, J=6.9 Hz, 3H), 2.08-1.95 (m, 1H), 1.90-1.45 (m, 3H).

Example 583:(R)-5-(3-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using a procedure analogous to Example1, steps C-H, 3-methyl-4-phenoxy-aniline in place of 3-cyclobutylanilinein step C, to yield the title compound. MS (ESI): mass calcd. forC₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.53-8.48 (d, J=6.5 Hz, 1H), 7.42-7.35 (m, 3H), 7.28-7.23 (dd, J=8.6,2.5 Hz, 1H), 7.18-7.12 (m, 1H), 7.06-7.01 (m, 3H), 6.51-6.46 (d, J=6.5Hz, 1H), 4.36-4.23 (m, 1H), 3.59-3.49 (m, 1H), 3.40-3.33 (m, 1H),3.05-2.94 (m, 2H), 2.37-2.31 (s, 3H), 2.16-2.05 (m, 2H), 1.95-1.72 (m,2H).

Example 584:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-chloro-4-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-C, and using 3-chloro-4-methylaniline in place of3-cyclobutylaniline in step A, to yield the title compound. MS (ESI):mass calcd. for C₂₄H₂₂ClN₅O₃S, 496.0; m/z found, 496.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆): δ 10.22 (br. s., 1H), 8.33 (d, J=5.56 Hz, 1H), 8.10(dd, J=7.83, 11.37 Hz, 1H), 7.64 (d, J=2.02 Hz, 1H), 7.59 (d, J=8.08 Hz,1H), 7.38 (dd, J=2.02, 8.08 Hz, 1H), 6.72-6.88 (m, 1H), 6.11 (d, J=16.67Hz, 1H), 6.07 (d, J=5.56 Hz, 1H), 5.69 (d, J=12.63 Hz, 1H), 4.43-4.53(m, 0.5H), 4.17-4.26 (m, 0.5H), 3.94-4.10 (m, 1H), 3.72-3.86 (m, 1H),2.91-3.16 (m, 1H), 2.60-2.84 (m, 1H), 2.43 (s, 3H), 1.90-1.99 (m, 1H),1.73-1.84 (m, 1H), 1.57-1.73 (m, 1H), 1.33-1.51 (m, 1H).

Example 585:(R)-4-Oxo-5-(2-phenylpyridin-4-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 2-phenylpyridin-4-amine in place of2-methyl-4-phenoxy-aniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₅H₂₂N₆O₂S, 470.5; m/z found, 471.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD and DMSO-d₆): δ 8.90-8.78 (m, 1H), 8.35-8.25 (m, 1H),8.09-8.01 (m, 3H), 7.49-7.37 (m, 4H), 6.30-6.16 (m, 1H), 4.22-4.18 (m,1H), 3.36-3.28 (m, 1H), 3.21-3.15 (m, 1H), 2.88-2.75 (m, 2H), 1.95-1.85(m, 2H), 1.76-1.57 (m, 2H).

Example 2:N-((3R,5R)-5-Hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (3R,5R)-tert-butyl3-hydroxy-5-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(Example 611) (2700 mg, 4.49 mmol) in DCM (20 mL) at room temperaturewas added TFA (75 mL) dropwise. The reaction was stirred at roomtemperature for 30 minutes. The reaction was concentrated to dryness andthe residue was purified by normal phase flash column chromatography(SiO₂) to give the title compound (2000 mg, 88.9% yield) as an off whitesolid. MS (ESI): mass calcd. for C₂₆H₂₃N₅O₄S, 501.6; m/z found, 502.2[M+H]+. ¹H NMR (400 MHz, CD₃OD): δ 8.30 (d, J=5.6 Hz, 1H), 8.03 (s, 1H)7.46-7.36 (m, 5H), 7.23-7.05 (m, 5H), 6.17 (d, J=5.6 Hz, 1H), 6.00 (s,1H), 4.69 (tt, J=11.8, 4.3 Hz, 1H), 4.30 (p, J=2.5 Hz, 1H), 3.56-3.46(m, 1H), 3.25 (ddt, J=13.1, 3.0, 1.6 Hz, 1H), 3.09 (dd, J=13.0, 1.8 Hz,1H), 2.90 (t, J=11.8 Hz, 1H), 2.17 (dtd, J=12.2, 4.0, 2.0 Hz, 1H), 2.00(bs, 1H), 1.89 (ddd, J=13.3, 12.0, 2.5 Hz, 1H).

Example 587:(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-[1,1′-Biphenyl]-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps C-H in Example 1, and using [1,1′-biphenyl]-3-amine(Intermediate 46) in place of 2-methyl-4-phenoxyaniline in step C, andusing (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₅H₂₁N₅O₂S,455.53; m/z found, 456.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.29 (d,J=5.6 Hz, 1H), 7.85-7.77 (m, 1H), 7.76-7.59 (m, 4H), 7.49-7.39 (m, 3H),7.39-7.30 (m, 1H), 6.18 (d, J=5.6 Hz, 1H), 4.63-4.5.3 (m, 1H), 3.65-3.51(m, 2H), 3.47-3.34 (m, 2H), 2.48-2.31 (m, 1H), 2.27-2.13 (m, 1H).

Step B:(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-([1,1′-biphenyl]-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.22 mmol) and formaldehyde (0.5 mL, 37 wt. % in H₂O) inmethanol (15 mL) was added NaBH(OAc)₃ (140 mg, 0.66 mmol) and wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated to dryness and purified by normal phase flash columnchromatography (SiO₂) to give the title compound as a yellow solid (73mg, 70% yield). MS (ESI): mass calcd. for C₂₆H₂₃N₅O₂S, 469.6; m/z found,470.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.43 (s, 1H), 8.30 (d, J=5.6Hz, 1H), 7.86-7.79 (m, 1H), 7.73-7.62 (m, 4H), 7.47-7.38 (m, 3H),7.37-7.31 (m, 1H), 6.19 (d, J=5.6 Hz, 1H), 4.67-4.50 (m, 1H), 3.70-3.58(m, 1H), 3.55-3.45 (m, 2H), 3.27-3.15 (m, 1H), 2.92 (s, 3H), 2.60-2.45(m, 1H), 2.30-2.15 (m, 1H).

Example 588:N-((3S,4S)-4-Methoxypyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(3S,4S)-3-amino-4-methoxy-pyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G,and TFA in place of HCl in step H to yield the title compound. MS (ESI):mass calcd. for C₂₆H₂₃N₅O₄S, 501.6; m/z found, 502.2 [M+H]⁺. ¹H NMR (500MHz, CDCL₃): δ 8.25 (d, J=5.5 Hz, 4H), 7.97-7.91 (m, 1H), 7.43-7.28 (m,4H), 7.21-7.04 (m, 5H), 6.07 (d, J=5.5 Hz, 1H), 4.66 (d, J=5.8 Hz, 1H),4.15-4.10 (m, 1H), 3.71-3.58 (m, 2H), 3.45 (s, 3H), 3.37 (d, J=12.6 Hz,1H).

Example 3:N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Method 1,Step I in Example 1 usingN-((3R,5R)-5-hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 586). MS (ESI): mass calcd. for C₂₉H₂₅N₅O₅S, 555.6; m/z found,556.2 [M+H]+. ¹H NMR (500 MHz, CDCl₃): δ 9.49 (s, 1H), 7.34 (dt, J=36.4,8.2 Hz, 4H), 7.20-7.05 (m, 5H), 6.82 (s, 1H), 6.63 (dt, J=29.6, 14.1 Hz,1H), 6.23 (d, J=16.5 Hz, 1H), 6.07-6.02 (m, 1H), 5.88 (d, J=4.9 Hz, 1H),5.64 (d, J=10.5 Hz, 2H), 4.40 (s, 1H), 3.74 (d, J=12.7 Hz, 1H), 3.53 (s,1H), 3.42 (s, 1H), 3.36 (d, J=12.8 Hz, 1H), 3.05 (hept, J=6.6 Hz, 2H),2.50 (q, J=7.2 Hz, 1H).

Example 590:(R,E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

In a microwave vial were added(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860) (300 mg, 0.618 mmol), 4-hydroxy-but-2-enoic acid (95 mg,0.92 mmol), DMF (7 mL), and HATU (705 mg, 1.85 mmol) and was heated inmicrowave at 100° C. for 5 minutes. The reaction was diluted with DCMand washed with water. The reaction was purified by normal phase flashcolumn chromatography (SiO₂) to give the title compound (70 mg, 20%yield). MS (ESI): mass calcd. for C₃₀H₂₇N₅O₅S, 569.6; m/z found, 570.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.44 (s, 1H), 8.28 (d, J=5.5 Hz, 1H),7.44-7.24 (m, 4H), 7.23-7.06 (m, 5H), 6.65 (d, J=16.5 Hz, 1H), 6.19 (d,J=6.3 Hz, 1H), 6.10 (d, J=5.5 Hz, 1H), 4.38-4.32 (m, 1H), 4.28 (s, 1H),4.04-3.90 (m, 2H), 3.74 (s, 1H), 3.56 (s, 1H), 3.39 (s, 1H), 3.24 (s,1H), 2.32 (s, 2H), 1.95 (s, 1H), 1.83-1.71 (m, 2H)

Example 591:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-cyclobutylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-C, and using 2-cyclobutylpyridin-4-amine in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₂₆H₂₆N₆O₃S,502.6; m/z found, 503.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.74-8.68 (d,J=5.3 Hz, 1H), 8.34-8.29 (d, J=5.6 Hz, 1H), 7.52-7.48 (d, J=1.9 Hz, 1H),7.42-7.37 (m, 1H), 6.85-6.74 (m, 1H), 6.24-6.16 (m, 2H), 5.78-5.67 (m,1H), 4.59-4.29 (m, 1H), 4.23-3.90 (m, 2H), 3.85-3.73 (m, 1H), 3.23-3.09(m, 1H), 2.95-2.82 (m, 1H), 2.47-2.33 (m, 4H), 2.18-2.02 (m, 2H),1.99-1.82 (m, 2H), 1.80-1.67 (m, 1H), 1.63-1.50 (m, 1H).

Example 592:(R)—N-(1-Cyanopiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860, 250 mg, 0.52 mmol), BrCN (65 mg, 0.62 mmol), andtriethylamine (0.143 mL, 1.03 mmol) in DCM (5 mL) was stirred at roomtemperature for 4 hours. The reaction was concentrated to dryness andthe residue was purified by normal phase flash column chromatography(SiO₂) to give the title compound (253 mg, 96.2% yield) as yellow solid.MS (ESI): mass calcd. for C₂₇H₂₂N₆O₃S, 510.6; m/z found, 511.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): δ 9.47 (s, 1H), 8.32 (d, J=5.5 Hz, 1H),7.44-7.35 (m, 2H), 7.36-7.25 (m, 2H), 7.22-7.07 (m, 4H), 6.10 (dd,J=29.2, 6.5 Hz, 2H), 4.21 (ddq, J=11.9, 8.0, 3.9 Hz, 1H), 3.57 (dd,J=12.4, 3.9 Hz, 1H), 3.36-3.26 (m, 1H), 3.18-3.04 (m, 2H), 1.97 (ddt,J=10.9, 7.4, 3.9 Hz, 2H), 1.81 (dddt, J=36.2, 13.8, 9.4, 3.9 Hz, 2H),1.62 (dtd, J=12.9, 9.0, 3.9 Hz, 1H).

Example 593:(R)—N-(1-(3-Methoxypropanoyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860) (300 mg, 0.618 mmol) in DCM (8 mL) at 0° C. was addedtriethylamine (0.389 mL, 2.80 mmol), followed by 3-methoxypropanoylchloride (70 mg, 0.57 mmol) and was stirred at 0° C. for 10 minutes. Thereaction was quenched with saturated aqueous NaHCO₃, extracted into DCM,dried over anhydrous Na₂SO₄, and concentrated to dryness. The residuewas purified by normal phase flash column chromatography (SiO₂) to givethe title compound (295 mg, 83.5% yield) as an off white solid. MS(ESI): mass calcd. for C₃₀H₂₉N₅O₅S, 571.7; m/z found, 572.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): δ 8.33 (dd, J=7.6, 5.4 Hz, 1H), 7.44-7.36 (m, 2H),7.29 (dq, J=12.2, 4.4, 3.7 Hz, 2H), 7.22-7.08 (m, 5H), 6.19-6.10 (m,2H), 5.90 (d, J=7.2 Hz, 1H), 4.13 (d, J=7.3 Hz, 1H), 3.90-3.55 (m, 3H),3.30 (s, 3H), 3.20 (td, J=18.1, 15.8, 9.4 Hz, 1H), 3.04 (hept, J=6.5 Hz,2H), 2.76 (dt, J=14.2, 6.8 Hz, 1H), 2.70-2.55 (m, 1H), 2.48 (q, J=7.2Hz, 1H), 2.06 (d, J=13.3 Hz, 1H), 2.00-1.90 (m, 1H), 1.65 (tdd, J=13.4,10.4, 6.1 Hz, 1H).

Example 594:N-(1-Cyanopiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 926) (350 mg, 0.721 mmol), BrCN (92 mg, 0.87 mmol), andtriethylamine (0.20 mL, 1.4 mmol) in DCM (5 mL) was stirred at roomtemperature for 4 hours. The reaction was concentrated to dryness andthe residue was purified by normal phase flash column chromatography(SiO₂) to give the title compound (360.5 mg, 97.96% yield) as yellowsolid. MS (ESI): mass calcd. for C₂₇H₂₂N₆O₃S, 510.6; m/z found, 511.15[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 8.32 (dd, J=6.2, 2.4 Hz, 1H),7.45-7.34 (m, 2H), 7.32-7.08 (m, 7H), 6.20-6.15 (m, 1H), 4.05 (tt,J=11.3, 3.9 Hz, 1H), 3.58 (s, 2H), 3.55-3.47 (m, 2H), 3.19 (td, J=12.8,2.7 Hz, 2H), 2.07-1.99 (m, 2H), 1.76 (td, J=12.2, 4.2 Hz, 2H).

Example 595:(R)-5-(3-Methyl-5-phenoxypyridin-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:2-Chloro-4-[(3-methyl-5-phenoxy-2-pyridyl)amino]pyridine-3-carbonitrile

To a microwave vial containing a stir bar,2-chloro-4-iodonicotinonitrile (1243 mg, 4.700 mmol), and3-methyl-5-phenoxy-pyridin-2-amine (890 mg, 4.44 mmol) were addedDPEPhos (102 mg, 0.190 mmol), Pd(OAc)₂ (46 mg, 0.21 mmol), and Cs₂CO₃(2530 mg, 7.765 mmol). The vial was treated with 1,4 dioxane (8 mL) viasyringe, then the entire mixture was degassed under vacuum for 1 minute,then vented to nitrogen. The reaction mixture was heated thermally at90° C. for 16 h. The reaction mixture was diluted with ether (100 mL)and filtered to remove the cesium carbonate. The filter cake was rinsedwith EtOAc (50 mL). The combined organics were dried over anhydrousNa₂SO₄, concentrated to dryness, and treated with DCM (50 mL). Thesoluble material was purified by flash column chromatography to give thetitle compound (230 mg, 14.5% yield).

Step B: (R)-tert-butyl3-(5-(3-methyl-5-phenoxypyridin-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

A microwave vial containing2-chloro-4-[(3-methyl-5-phenoxy-2-pyridyl)amino]pyridine-3-carbonitrile(806 mg, 2.39 mmol), Cs₂CO₃ (2011 mg, 6.172 mmol), and dioxane (5 mL)was sealed, and treated with dioxane (5 mL) via syringe. To the reactionwas added tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate22) (6.78 mmol), and was degassed under vacuum, vented to N₂, and heatedat 122° C. for 1 h. The reaction mixture was treated with solid CDI(2000 mg, 12.33 mmol) in one portion, resealed and stirred at 70° C. for60 min. The reaction was diluted with EtOAc (100 mL) and DCM (100 mL),washed with saturated aqueous sodium bicarbonate, and the organic layercollected. The aqueous layer was extracted again with EtOAc (100 mL),and the combined organics were dried over anhydrous MgSO₄, concentratedto dryness, and purified by flash column chromatography to give thetitle compound as an orange foam (712 mg, 49.5% yield).

Step C:(R)-5-(3-Methyl-5-phenoxypyridin-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (R)-tert-butyl3-(5-(3-methyl-5-phenoxypyridin-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(710 mg, 1.18 mmol) in dioxane (5 mL) was treated with 4 M HCl-dioxane(5 mL). The reaction mixture was stirred at room temperature for 1.5 h.The reaction was then treated slowly with ether (15 mL), and theresulting suspension was stirred for 10 min at room temperature,filtered, and dried under vacuum to give the title compound as a yellowsolid (672 mg, 99.1% yield). MS (ESI): mass calcd. for C₂₆H₂₄N₆O₃S,500.6; m/z found, 501.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.58-8.53 (d,J=6.5 Hz, 1H), 8.25-8.21 (d, J=3.4 Hz, 1H), 7.56-7.52 (d, J=2.7 Hz, 1H),7.51-7.45 (m, 2H), 7.30-7.25 (m, 1H), 7.22-7.17 (m, 2H), 6.48-6.44 (dd,J=6.5, 0.9 Hz, 1H), 4.35-4.25 (m, 1H), 3.58-3.51 (m, 1H), 3.39-3.33 (m,1H), 3.06-2.96 (m, 2H), 2.28-2.22 (s, 3H), 2.15-2.05 (m, 2H), 1.93-1.75(m, 2H).

Example 596:(E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

In a microwave vial were added4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 926) (300 mg, 0.618 mmol), 4-hydroxy-but-2-enoic acid (95 mg,0.93 mmol), DMF (7 mL), and HATU (705 mg, 1.85 mmol). The reaction washeated in microwave at 100° C. for 5 minutes. The reaction was dilutedwith DCM and washed with water. The reaction was purified by normalphase flash column chromatography (SiO₂) to give the title compound(61.5 mg, 17.5% yield). MS (ESI): mass calcd. for C₃₀H₂₇N₅O₅S, 569.6;m/z found, 570.10 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 8.31 (d, J=5.5 Hz,1H), 8.03 (s, 1H), 7.45-7.35 (m, 2H), 7.30 (dd, J=9.3, 2.6 Hz, 2H),7.24-7.09 (m, 5H), 6.88 (dt, J=15.2, 3.8 Hz, 1H), 6.59 (dt, J=15.3, 2.1Hz, 1H), 6.17 (dd, J=5.8, 2.2 Hz, 1H), 4.65 (d, J=13.3 Hz, 1H), 4.30(dd, J=3.8, 2.1 Hz, 2H), 4.23-4.10 (m, 2H), 3.94 (s, 3H), 3.23 (t,J=12.8 Hz, 1H), 2.83 (t, J=12.6 Hz, 1H), 2.06 (t, J=15.7 Hz, 2H), 1.52(d, J=12.4 Hz, 1H).

Example 597:N-(1-(3-Methoxypropanoyl)piperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 926) (300 mg, 0.618 mmol) in DCM (8 mL) at 0° C. was addedtriethylamine (0.389 mL, 2.80 mmol), followed by 3-methoxypropanoylchloride (70 mg, 0.57 mmol). The reaction was stirred at 0° C. for 10minutes. The reaction was quenched with saturated aqueous NaHCO₃ andextracted into DCM. The organic layer was dried over anhydrous Na₂SO₄,concentrated to dryness, and the residue was purified by normal phaseflash column chromatography (SiO₂) to give the title compound (207.3 mg,58.7% yield) as an off white solid. MS (ESI): mass calcd. forC₃₀H₂₉N₅O₅S, 571.7; m/z found, 572.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ9.48 (s, 1H), 8.35 (d, J=5.5 Hz, 1H), 7.47-7.36 (m, 2H), 7.32-7.26 (m,2H), 7.22-7.08 (m, 5H), 6.15 (d, J=5.5 Hz, 1H), 5.97-5.91 (m, 1H),4.70-4.62 (m, 1H), 4.18 (tdt, J=11.5, 8.0, 4.2 Hz, 1H), 3.94 (dd,J=11.2, 6.7 Hz, 1H), 3.71 (q, J=6.4 Hz, 2H), 3.35 (s, 3H), 3.23-3.13 (m,1H), 2.76 (td, J=13.0, 2.9 Hz, 1H), 2.63 (td, J=6.5, 2.8 Hz, 2H), 2.13(d, J=12.6 Hz, 1H), 2.04 (dd, J=13.4, 4.0 Hz, 1H), 1.46 (dd, J=12.6, 4.1Hz, 2H).

Example 598:(R)—N-(1-Acryloylpiperidin-3-yl)-3-amino-4-((3-cyclobutoxyphenyl)amino)thieno[2,3-b]pyridine-2-carboxamide

The title compound was prepared using methods analogous to Example 33Steps A-D and using 3-nitrophenol and bromocyclobutane in place of4-nitrophenol and 2-iodopropane in step A. MS (ESI): mass calcd. forC₂₇H₂₇N₅O₄S, 517.6; m/z found, 518.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.31-8.24 (m, 1H), 7.51-7.41 (m, 1H), 7.09-6.89 (m, 3H), 6.85-6.73 (m,1H), 6.23-6.14 (m, 1H), 6.13-6.08 (m, 1H), 5.78-5.63 (m, 1H), 4.78-4.67(m, 1H), 4.57-3.86 (m, 3H), 3.24-3.09 (m, 1H), 2.94-2.80 (m, 1H),2.51-2.39 (m, 2H), 2.18-1.99 (m, 3H), 1.92-1.79 (m, 2H), 1.78-1.62 (m,2H), 1.61-1.50 (m, 1H).

Example 599:(R)-5-([1,1′-Biphenyl]-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 3-phenylaniline in place of2-methyl-4-phenoxy-aniline in step C, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₅H₂₁N₅O₂S, 455.14; m/z found, 456.3 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.29 (d, J=5.6 Hz, 1H), 7.85-7.77 (m, 1H), 7.76-7.59(m, 4H), 7.49-7.39 (m, 3H), 7.39-7.30 (m, 1H), 6.18 (d, J=5.6 Hz, 1H),4.63-4.5.3 (m, 1H), 3.65-3.51 (m, 2H), 3.47-3.34 (m, 2H), 2.48-2.31 (m,1H), 2.27-2.13 (m, 1H).

Example 600:2-((1-Acryloylpiperidin-3-yl)amino)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

To solution of2-amino-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one(Intermediate 56, 100 mg, 0.257 mmol) and prop-2-enoylpiperidin-3-one(Intermediate 79) (47.2 mg, 0.308 mmol) in anhydrous methanol (4 mL) wasadded acetic acid (0.05 mL) at room temperature under N₂ and was stirredfor 1 h. To the reaction mixture was added BH₃-pyridine complex (35.8mg, 0.386 mmol) at room temperature and was stirred overnight at roomtemperature under N₂. The reaction mixture was purified by flash columnchromatography to give the title compound as a light yellow solid (51mg, 33% yield). MS (ESI): mass calcd. for C₂₉H₂₇N₅O₃S, 525.6; m/z found,526.4 [M+H]⁺.

Example 601:(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(2-(methylamino)acetyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)-5-([1,1′-biphenyl]-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamidewas prepared using Method 1, steps C-G in Example 1, and using3-phenylaniline in place of 2-methyl-4-phenoxy-aniline in step C. Thetitle compound was prepared using a method analogous to Example 75 usingand using 2-[tert-butoxycarbonyl(methyl)amino]acetic acid (Intermediate21) followed by treatment of the purified solid with 6NHCl/MeOH andpurification by column chromatography eluting with water (0.1%HCOOH)/MeOH to provide the desired compound as a light yellow solid. MS(ESI): mass calcd. for C₂₈H₂₆N₆O₃S, 526.6; m/z found, 527.4 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.48 (s, 1H), 8.31-8.22 (m, 1H), 7.85-7.76 (m,1H), 7.75-7.57 (m, 4H), 7.48-7.28 (m, 4H), 6.23-6.08 (m, 1H), 4.66-4.53(m, 1H), 3.92-3.87 (m, 2H), 3.84-3.61 (m, 2H), 3.60-3.39 (m, 2H),2.74-2.64 (m, 3H), 2.38-2.02 (m, 2H).

Example 602:(R)-4-Oxo-5-(2-phenylpyridin-4-yl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 2-phenylpyridin-4-amine in place of2-methyl-4-phenoxy-aniline in step C, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₄H₂₀N₆O₂S, 456.5; m/z found, 457.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆ and CD₃OD): δ 8.77-8.74 (m, 1H), 8.09-8.06 (m, 1H),8.05-8.01 (m, 2H), 7.90-7.87 (m, 1H), 7.45-7.37 (m, 3H), 7.31-7.28 (m,1H), 6.03-5.98 (m, 1H), 4.52-4.42 (m, 1H), 3.35-3.27 (m, 2H), 3.19-3.16(m, 1H), 3.15-3.13 (m, 1H), 2.24-2.14 (m, 1H), 2.03-1.94 (m, 1H).

Example 603:(R)-5-(3-Cyclobutylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-B. MS (ESI): mass calcd. for C₂₄H₂₅N₅O₂S, 447.6; m/z found,448.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.53-8.46 (d, J=6.6 Hz, 1H),7.60-7.54 (t, J=7.8 Hz, 1H), 7.51-7.45 (m, 1H), 7.38-7.33 (s, 1H),7.30-7.24 (m, 1H), 6.44-6.37 (d, J=6.6 Hz, 1H), 4.37-4.27 (m, 1H),3.71-3.62 (m, 1H), 3.57-3.51 (dd, J=12.4, 4.0 Hz, 1H), 3.39-3.33 (m,1H), 3.06-2.97 (m, 2H), 2.44-2.34 (m, 2H), 2.25-2.16 (m, 2H), 2.14-2.03(m, 3H), 1.94-1.77 (m, 3H).

Example 604:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenylpyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 6-phenylpyridin-2-amine in place of2-methyl-4-phenoxy-aniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₈H₂₄N₆O₃S, 524.6; m/z found, 525.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 10.24 (s, 1H), 8.34-8.27 (m, 1H), 8.20-8.07 (m, 3H),8.06-8.02 (m, 2H), 7.58-7.52 (m, 1H), 7.50-7.41 (m, 3H), 6.82-6.69 (m,1H), 6.23-6.16 (m, 1H), 6.11-6.03 (m, 1H), 5.68-5.62 (m, 1H), 4.50-4.09(m, 1H), 4.09-3.88 (m, 1H), 3.86-3.68 (m, 1H), 3.11-2.93 (m, 1H),2.80-2.62 (m, 1H), 1.96-1.89 (m, 1H), 1.79-1.72 (m, 1H), 1.71-1.57 (m,1H), 1.46-1.35 (m, 1H).

Example 605:(R)-5-(4-Cyclobutoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(3-amino-4-((4-cyclobutoxy-2-methylphenyl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate

To a sealed tube containing2-chloro-4-((4-cyclobutoxy-2-methylphenyl)amino)nicotinonitrile(Intermediate 34, 481 mg, 1.53 mmopl) was added a 0.5 M solution of(R)-tert-butyl 3-(2-mercaptoacetamido)piperidine-1-carboxylate(Intermediate 22) (3.68 mL, 1.84 mmol) in dioxane. The suspension washeated in the sealed tube in a 150° C. aluminum block for 15 minutes.The reaction mixture was cooled in a water bath to give the titlecompound (845 mg), which was used directly in the next reaction withoutany workup.

Step B: (R)-tert-Butyl3-(5-(4-cyclobutoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To (R)-tert-butyl3-(3-amino-4-((4-cyclobutoxy-2-methylphenyl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate(845 mg, 1.53 mmol) in dioxane was added CDI (0.994 g, 6.13 mmol). Thetube was sealed and the vessel was evacuated and refilled with argontwice. The mixture was heated at 150° C. for 10 minutes, then themixture was cooled to room temperature. The mixture was partitionedbetween EtOAc (50 mL) and water (50 mL). The aqueous phase was extractedwith EtOAc (2×50 mL) and the combined organic extracts were washed with1 M aqueous HCl (50 mL), followed by saturated aqueous NaCl (50 mL). Theorganic phase was dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by flash columnchromatography to give the title compound as a tan solid (524.5 mg, 59%yield).

Step C:(R)-5-(4-Cyclobutoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (R)-tert-butyl3-(5-(4-cyclobutoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(521.4 mg, 0.903 mmol) in dioxane (4 mL) was added 4 M HCl in dioxane (4mL) and the solution was stirred at room temperature for 30 minutes. Thereaction mixture was concentrated to dryness and the solid was driedunder vacuum to give a tan powder (556.9 mg). A 100 mg of the sample waspurified by flash column chromatography to give a tan powder (70.6 mg).The material was re-purified by RP-HPLC and the pooled fractions werepartially concentrated to remove CH₃CN, then were made basic withsaturated aqueous NaHCO₃, and extracted twice with DCM. The organicphase was dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was dried under vacuum at 60° C. to give the titlecompound as a light yellow solid (31.3 mg). MS (ESI): mass calcd. forC₂₅H₂₇N₅O₃S, 477.6; m/z found, 478.2 [M+H]⁺. 1H NMR (400 MHz,CHLOROFORM-d) δ 8.33 (d, J=5.56 Hz, 1H), 7.08-7.12 (m, 1H), 6.83 (d,J=2.53 Hz, 1H), 6.79 (dd, J=3.03, 8.59 Hz, 1H), 6.13-6.24 (m, 1H), 5.99(d, J=5.05 Hz, 1H), 4.67 (quin, J=7.07 Hz, 1H), 4.08-4.18 (m, 1H), 3.08(d, J=12.13 Hz, 1H), 2.72-2.91 (m, 3H), 2.42-2.52 (m, 2H), 2.14-2.26 (m,2H), 2.12 (s, 3H), 1.66-1.95 (m, 6H), 1.50-1.63 (m, 1H).

Example 606:2-((1-Acryloylpiperidin-4-yl)amino)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

The title compound was prepared using conditions analagous to Example600 using 1-prop-2-enoylpiperidin-4-one (Intermediate 80). MS (ESI):mass calcd. for C₂₉H₂₇N₅O₃S, 525.6; m/z found, 526.5 [M+H]⁺. 1H NMR (400MHz, DMSO-d6): δ 7.96 (d, J=5.4 Hz, 1H), 7.47-7.37 (m, 2H), 7.29 (d,J=8.5 Hz, 1H), 7.20-7.14 (m, 1H), 7.11-7.06 (m, 2H), 7.06-7.02 (m, 1H),6.96-6.86 (m, 1H), 6.87-6.74 (m, 1H), 6.12-6.00 (m, 1H), 5.70 (d, J=5.4Hz, 1H), 5.67-5.58 (m, 1H), 4.94-4.78 (m, 1H), 4.25-4.10 (m, 1H),4.00-3.87 (m, 1H), 3.22-3.18 (m, 1H), 2.99-2.87 (m, 1H), 2.05 (s, 3H),1.97-1.88 (m, 2H), 1.37-1.25 (m, 2H).

Example 607:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-C, and using 4-methyl-3-(trifluoromethyl)aniline in placeof 3-cyclobutylaniline in step A. MS (ESI): mass calcd. forC₂₅H₂₂F₃N₅O₃S, 529.5; m/z found, 530.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 10.23 (br. s., 1H), 8.33 (d, J=5.56 Hz, 1H), 8.06-8.17 (m,1H), 7.88 (s, 1H), 7.67-7.73 (m, 2H), 6.72-6.88 (m, 1H), 6.11 (d,J=16.67 Hz, 1H), 6.05 (d, J=5.56 Hz, 1H), 5.69 (dd, J=2.27, 10.36 Hz,1H), 4.43-4.54 (m, 0.5H), 4.16-4.26 (m, 0.5H), 3.96-4.10 (m, 1H),3.73-3.86 (m, 1H), 2.92-3.17 (m, 1H), 2.61-2.83 (m, 1H), 2.55 (m, 3H),1.89-1.99 (m, 1H), 1.73-1.85 (m, 1H), 1.57-1.74 (m, 1H), 1.43 (m, 1H).

Example 608:5-(4-Isopropoxy-2-methylphenyl)-4-oxo-N—((R)-1-((E)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using methods analogous to Example 33,Steps A-D using(E)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoicacid (Intermediate 72) in Step D. MS (ESI): mass calcd. for C₃₄H₄₀N₆O₆S,660.8; m/z found, 661.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.31-8.24 (m,1H), 7.24-7.17 (m, 1H), 6.98-6.87 (m, 2H), 6.80-6.56 (m, 2H), 6.04-5.96(m, 1H), 4.70-4.58 (m, 1H), 4.20-3.84 (m, 5H), 3.80-3.63 (m, 2H),3.58-3.32 (m, 4H), 3.24-3.05 (m, 1H), 3.04-2.72 (m, 5H), 2.13-1.97 (m,4H), 1.92-1.65 (m, 2H), 1.65-1.51 (m, 1H), 1.38-1.28 (m, 6H).

Example 609:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-cyclobutoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)-5-(4-Cyclobutoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 605) was purified by Chiral Resolution Method A to obtain the*S atropisomer, followed by Step H in Example 1, Method 1, to yield thetitle compound. MS (ESI): mass calcd. for C₂₈H₂₉N₅O₄S, 531.6; m/z found,532.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30 (d, J=5.56 Hz, 1H), 7.20(d, J=8.59 Hz, 1H), 6.91 (d, J=2.53 Hz, 1H), 6.74-6.88 (m, 2H), 6.21(dd, J=3.03, 16.67 Hz, 1H), 6.02 (d, J=5.56 Hz, 1H), 5.74 (t, J=8.59 Hz,1H), 4.75 (quin, J=7.07 Hz, 1H), 4.50-4.59 (m, 0.5H), 4.26-4.36 (m,0.5H), 4.14-4.23 (m, 0.5H), 3.90-4.05 (m, 1.5H), 3.11-3.24 (m, 1H),2.82-2.98 (m, 1H), 2.43-2.56 (m, 2H), 2.01-2.24 (m, 6H), 1.82-1.93 (m,2H), 1.68-1.82 (m, 2H), 1.52-1.68 (m, 1H).

Example 610:(R)-4-Oxo-5-(4-phenylpyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 4-phenylpyridin-2-amine in place of2-methyl-4-phenoxy-aniline in step C and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₅H₂₂N₆O₂S, 470.5; m/z found, 471.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.75-8.66 (m, 1H), 8.34-8.30 (m, 1H), 7.95-7.87 (m, 2H),7.83-7.78 (m, 2H), 7.54-7.44 (m, 3H), 6.28-6.22 (m, 1H), 4.31-4.19 (m,1H), 3.56-3.47 (m, 1H), 3.37-3.34 (m, 1H), 3.00-2.88 (m, 2H), 2.16-2.01(m, 2H), 1.86-1.67 (m, 2H).

Example 4: (3R,5R)-tert-Butyl3-hydroxy-5-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a dry flask were added (3R,5R)-tert-butyl3-amino-5-hydroxypiperidine-1-carboxylate (Intermediate 04) (2.00 g,7.91 mmol), diisopropylethylamine (3.778 mL, 21.58 mmol), and THF (29mL) and was cooled to 0° C.4-Oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride (Intermediate 40) (3.035 g, 7.194 mmol) was added dropwise at0° C. The reaction was monitored by LCMS and when it had gone tocompletion, the reaction was quenched with saturated NaHCO₃, extractedwith DCM, and concentrated to dryness. The residue was purified bynormal phase flash column chromatography (SiO₂) to give the titlecompound (2880 mg, 66.5% yield). MS (ESI): mass calcd. for C₃₁H₃₁N₅O₆S,601.7; m/z found, 602.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 9.48 (s, 1H),8.32 (d, J=5.6 Hz, 1H), 7.44-7.36 (m, 2H), 7.30 (dt, J=13.9, 5.7 Hz,2H), 7.22-7.08 (m, 5H), 6.13 (d, J=5.5 Hz, 1H), 5.98 (s, 1H), 4.35 (d,J=5.2 Hz, 1H), 3.99 (s, 1H), 3.73 (s, 2H), 3.55 (s, 2H), 3.24 (s, 1H),2.00-1.75 (m, 2H), 1.49 (s, 9H).

Example 612:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(oxetan-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: Methyl5-(4-(oxetan-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

The title compound was prepared using the procedure found in Example534, step A, and using 4-(oxetan-3-yloxy)aniline and methyl2-sulfanylacetate in place of 3-cyclobutylaniline and tert-butyl(3R)-3-[(2-sulfanylacetyl)amino]piperidine-1-carboxylate (Intermediate22), to yield the title compound (2.093 g, 88.07% yield).

Step B: Lithium5-(4-(oxetan-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

To a round bottom flask were added methyl5-(4-(oxetan-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(2.0 g, 5.0 mmol) and THF (40 mL) and with stirring was added 2.0equivalents of LiOH (2 M solution, 5.033 mL, 10.07 mmol). After 20 min,MeOH (10 mL) was added and was heated at 60° C. for 2 h, then water (10mL) was added and was heated at 70° C. for 30 min, then heated at 60° C.for 4 h, and overnight at rt. The next day, it was heated at 60° C. for6 h longer and allowed to cool to rt. The reaction mixture wasconcentrated to dryness and was evaporated to dryness several times withMeOH to get rid of excess solvents. The residue was dissolved in MeOH(10 mL) and the product was precipitated using ether (˜800 mL). Theprecipitate was collected by filtration and dried to give the titlecompound as a brown solid (2.007 g, 102.4% yield).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(oxetan-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a 40 mL vial were added lithium5-(4-(oxetan-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(250 mg, 0.64 mmol), 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one(Intermediate 15), THF (3.0 mL), and diisopropylethylamine (1.0 mL, 6.4mmol) and while stirring at rt was added 1-propanephosphonic anhydride(1.28 mL, 1.93 mmol) and was stirred overnight at rt. The reactionmixture was extracted with EtOAc (3×) and DCM. The combined organicphases were washed with water and brine, dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness. The residue was purified by flashcolumn chromatography, then by basic HPLC to give the title compound asa yellow solid (43 mg, 13% yield). MS (ESI): mass calcd. forC₂₆H₂₅N₅O₅S, 519.6; m/z found, 520.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.18 (d, J=5.4 Hz, 1H), 7.26 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H),6.79-6.63 (m, 1H), 6.10 (d, J=16.8 Hz, 1H), 6.01 (d, J=5.6 Hz, 1H),5.70-5.59 (m, 1H), 5.31-5.22 (m, 1H), 5.03-4.91 (m, 2H), 4.68-4.60 (m,2H), 4.45 (d, J=14.6 Hz, 0.5H), 4.21 (d, J=12.3 Hz, 0.5H), 4.08 (d,J=13.2 Hz, 0.5H), 3.95-3.81 (m, 1.5H), 3.15-3.03 (m, 1H), 2.87-2.74 (m,1H), 2.02-1.95 (m, 1H), 1.87-1.74 (m, 1H), 1.71-1.59 (m, 1H), 1.55-1.43(m, 1H).

Example 613:(R)-5-(3-(Cyclopentyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using methods analogous to Example 33using 3-nitrophenol and bromocyclopentane in Steps A-C to yield2-chloro-4-((3-cyclopentylphenyl)amino)nicotinonitrile. This wassubjected to Method 1, steps C-H, in Example 1, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₅H₂₇N₅O₃S, 477.6; m/z found, 478.2 [M+H]⁺. ¹H NMR (400MHz, CD3OD and DMSO-d₆): δ 8.50 (s, 1H), 8.39-8.35 (m, 1H), 7.57-7.48(m, 1H), 7.16-7.08 (m, 1H), 7.04-6.97 (m, 2H), 6.20-6.15 (m, 1H),4.93-4.86 (m, 1H), 4.35-4.24 (m, 1H), 3.48-3.40 (m, 1H), 3.34-3.30 (m,1H), 2.99-2.86 (m, 2H), 2.08-1.95 (m, 4H), 1.90-1.78 (m, 6H), 1.72-1.63(m, 2H).

Example 614:N-((3S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared analogous to Example 33 using tert-butyl(3S,4R)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate in place oftert-butyl (3R)-3-aminopiperidine-1-carboxylate in the referenced StepG, to yield the title compound. MS (ESI): mass calcd. for C₂₆H₂₇N₅O₅S,521.6; m/z found, 522.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.29 (d,J=5.5 Hz, 1H), 7.31-7.15 (m, 1H), 7.01-6.85 (m, 2H), 6.70-6.50 (m, 1H),6.38-6.20 (m, 1H), 6.02 (d, J=5.5 Hz, 1H), 5.83-5.69 (m, 1H), 4.74-4.36(m, 3H), 4.13-3.47 (m, 4H), 2.10 (s, 3H), 1.42-1.30 (m, 6H).

Example 5:N-(trans-3-Hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of trans-tert-butyl3-hydroxy-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(Example 617) (1200 mg, 2.00 mmol) in DCM (20 mL) at room temperaturewas added TFA (34 mL) dropwise. The reaction was stirred at roomtemperature for 30 minutes. The reaction was concentrated to dryness andthe residue was purified by normal phase flash column chromatography(SiO₂) to give the title compound (905 mg, 90.5% yield) as an off whitesolid. MS (ESI): mass calcd. for C₂₆H₂₃N₅O₄S, 501.6; m/z found, 502.2[M+H]+. ¹H NMR (500 MHz, CDCl₃): δ 8.30-8.21 (m, 1H), 7.72 (s, 1H), 7.55(s, 2H), 7.41 (tt, J=18.0, 8.9 Hz, 4H), 7.29 (d, J=11.2 Hz, 1H), 7.16(ddt, J=27.3, 18.8, 9.9 Hz, 3H), 6.16-6.07 (m, 1H), 3.91 (s, 1H), 3.55(d, J=12.8 Hz, 1H), 3.45-3.37 (m, 5H), 3.07 (dd, J=20.2, 10.1 Hz, 1H),2.95 (d, J=12.0 Hz, 1H), 2.20 (d, J=15.2 Hz, 1H).

Example 616:(R)-5-(3-(Cyclohexyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using cyclohexyl methanesulfonate and3-nitrophenol in place of phenol and 5-fluoro-2-nitrotoluene in step A,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G.MS (ESI): mass calcd. for C₂₆H₂₉N₅O₃S, 491.6; m/z found, 492.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ 8.01 (d, J=5.7 Hz, 1H), 7.48-7.33 (m, 1H),7.04-6.93 (m, 1H), 6.89-6.77 (m, 2H), 5.87 (d, J=5.7 Hz, 1H), 4.40-4.28(m, 1H), 4.02-3.89 (m, 1H), 3.22-3.10 (m, 1H), 2.95-2.82 (m, 1H),2.69-2.49 (m, 2H), 2.09-1.92 (m, 3H), 1.83-1.73 (m, 3H), 1.71-1.62 (m,1H), 1.61-1.48 (m, 4H), 1.44-1.28 (m, 3H).

Example 6: trans-tert-Butyl3-hydroxy-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a dry flask were added trans-4-amino-1-boc-3-hydroxypiperidine (1.00g, 4.62 mmol), diisopropylethylamine (2.207 mL, 12.61 mmol), and THF (17mL) and was cooled to 0° C.4-Oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride (Intermediate 40) (1.773 g, 4.203 mmol) was added dropwise at0° C. The reaction was monitored by LCMS and when it had gone tocompletion, the reaction was quenched with saturated NaHCO₃, extractedwith DCM, and concentrated to dryness. The residue was purified bynormal phase flash column chromatography (SiO₂) to give the titlecompound. (1700 mg, 67.2% yield). MS (ESI): mass calcd. for C₃₁H₃₁N₅O₆S,601.7; m/z found, 602.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 8.17 (d,J=5.5 Hz, 1H), 7.55 (dd, J=9.0, 2.5 Hz, 1H), 7.44-7.36 (m, 2H), 7.26(dd, J=8.6, 2.5 Hz, 1H), 7.22-7.06 (m, 6H), 6.14 (d, J=7.3 Hz, 1H), 6.03(d, J=5.5 Hz, 1H), 4.36 (s, 2H), 4.12 (q, J=7.2 Hz, 1H), 3.93 (dd,J=14.2, 7.5 Hz, 1H), 3.60 (td, J=10.1, 5.0 Hz, 1H), 2.73 (s, 1H), 2.62(s, 1H), 2.04 (s, 2H), 1.45 (s, 9H).

Example 618: (R)-4-Oxo-5-(5-phenylpyridin-3-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 5-phenylpyridin-3-amine in Step C andtert-butyl (3R)-3-aminopiperidine-1-carboxylate Step G. MS (ESI): masscalcd. for C₂₅H₂₂N₆O₂S, 470.5; m/z found, 471.3 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.97-8.91 (m, 1H), 8.61-8.53 (m, 1H), 8.51 (s, 1H), 8.28-8.22(m, 1H), 8.21-8.16 (m, 1H), 7.74-7.68 (m, 2H), 7.52-7.41 (m, 3H),6.20-6.13 (m, 1H), 4.23-4.13 (m, 1H), 3.42-3.34 (m, 1H), 3.23-3.13 (m,1H), 2.97-2.82 (m, 2H), 2.08-1.95 (m, 2H), 1.81-1.67 (m, 2H).

Example 619:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-Phenoxypyrimidin-5-amine

The title compound was prepared in a manner analogous to Method 1, stepsA-B in Example 1, and using 2-chloro-5-nitro-pyrimidine in place of5-fluoro-2-nitrotoluene in step A, to yield the title compound.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1 using 2-phenoxypyrimidin-5-amine in Step C, and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₂H₂₁N₇O₄S, 479.5; m/z found, 480.4 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.71 (s, 2H), 8.35-8.30 (m, 1H), 6.83-6.68 (m, 1H),6.34-6.24 (m, 1H), 6.22-6.12 (m, 1H), 5.77-5.64 (m, 1H), 4.45-3.75 (m,6H), 3.20-3.06 (m, 1H), 2.94-2.80 (m, 1H), 2.11-1.99 (m, 1H), 1.90-1.80(m, 1H), 1.79-1.64 (m, 1H), 1.62-1.48 (m, 1H).

Example 620:(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsB-H in Example 1, and using 1-nitro-3-(trifluoromethoxy)benzene in placeof 2-methyl-1-nitro-4-phenoxy-benzene in step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₁H₁₈F₃N₅O₃S, 477.5; m/z found, 478.1 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.04 (d, J=5.7 Hz, 1H), 7.69-7.59 (m, 1H), 7.42-7.33(m, 2H), 7.32-7.25 (m, 1H), 5.87 (d, J=5.7 Hz, 1H), 4.01-3.91 (m, 1H),3.22-3.11 (m, 1H), 2.92-2.83 (m, 1H), 2.65-2.54 (m, 2H), 2.08-1.99 (m,1H), 1.83-1.75 (m, 1H), 1.71-1.52 (m, 2H).

Example 621:(R)-5-(3-Cyclobutoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 1-cyclobutoxy-3-nitrobenzene

The title compound was prepared using a method analogous to Example 33Step A and using 3-nitrophenol and bromocyclobutane in place of4-nitrophenol and 2-iodopropane

Step B:(R)-5-(3-Cyclobutoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using methods analogous to Method 1,Example 1 Steps B-H. MS (ESI): mass calcd. for C₂₄H₂₅N₅O₃S, 463.6; m/zfound, 464.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.46 (s, 1H), 8.31-8.25(m, 1H), 7.52-7.43 (m, 1H), 7.05-6.89 (m, 3H), 6.16-6.08 (m, 1H),4.77-4.66 (m, 1H), 4.31-4.18 (m, 1H), 3.57-3.45 (m, 1H), 3.37-3.32 (m,1H), 3.02-2.85 (m, 2H), 2.53-2.40 (m, 2H), 2.20-1.97 (m, 4H), 1.90-1.65(m, 4H).

Example 622:(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(pyridin-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedure found in Example540, steps A-B. MS (ESI): mass calcd. for C₂₅H₂₂N₆O₂S, 470.5; m/z found,471.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.8.92-8.88 (m, 1H), 8.77-8.66(m, 1H), 8.52-8.40 (m, 2H), 8.25-8.05 (m, 3H), 8.01-7.93 (m, 1H),7.89-7.80 (m, 1H), 6.45 (d, J=6.1 Hz, 1H), 4.38-4.25 (m, 1H), 3.58-3.50(m, 1H), 3.40-3.33 (m, 1H), 3.06-2.96 (m, 2H), 2.16-2.04 (m, 2H),1.93-1.75 (m, 2H).

Example 623:(R)-4-Oxo-5-(6-phenylpyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 3-phenylaniline in place of2-methyl-4-phenoxy-aniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₅H₂₂N₆O₂S, 470.5; m/z found, 471.1 [M+H]⁺. ¹H NMR (400MHz, CD3OD and DMSO-d₆): δ 8.31-8.27 (m, 1H), 8.13-8.04 (m, 2H),8.02-7.97 (m, 2H), 7.50-7.46 (m, 1H), 7.45-7.38 (m, 3H), 6.24-6.19 (m,1H), 4.20-4.16 (m, 1H), 3.35-3.29 (m, 1H), 3.20-3.15 (m, 1H), 2.88-2.75(m, 2H), 1.95-1.85 (m, 2H), 1.76-1.57 (m, 2H).

Example 624:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example505, except the *R atropisomer was obtained. MS (ESI): mass calcd. forC₂₅H₂₂F₃N₅O₄S, 545.5; m/z found, 546.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):δ 8.32 (d, J=5.56 Hz, 1H), 7.48 (d, J=8.59 Hz, 1H), 7.43 (s, 1H), 7.35(d, J=9.09 Hz, 1H), 6.73-6.87 (m, 1H), 6.21 (dd, J=3.28, 16.93 Hz, 1H),6.02 (d, J=5.56 Hz, 1H), 5.74 (t, J=8.34 Hz, 1H), 4.53 (d, J=2.53 Hz,0.5H), 4.31 (d, J=12.63 Hz, 0.5H), 4.14-4.23 (m, 0.5H), 3.88-4.07 (m,1.5H), 3.15-3.26 (m, 1H), 2.81-3.02 (m, 1H), 2.22 (s, 3H), 2.02-2.14 (m,1H), 1.83-1.95 (m, 1H), 1.66-1.84 (m, 1H), 1.50-1.66 (m, 1H).

Example 625: (3S,4S)-tert-Butyl3-fluoro-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidine-1-carboxylate

To a dry flask were added (3S,4S)-tert-butyl3-amino-4-fluoropyrrolidine-1-carboxylate (241 mg, 1.185 mmol),diisopropylethylamine (0.622 mL, 3.56 mmol), and THF (5 mL) and wascooled to 0° C.4-Oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride (Intermediate 40) (0.500 g, 1.18 mmol) was added dropwise at 0°C. The reaction was monitored by LCMS and when it had gone tocompletion, the reaction was quenched with saturated NaHCO₃, extractedwith DCM, and concentrated to dryness. The residue was purified bynormal phase flash column chromatography (SiO₂) to give the titlecompound (480 mg, 69% yield) as an off white solid. MS (ESI): masscalcd. for C₃₀H₂₈FN₅O5S, 589.6; m/z found, 590.2 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): δ 9.56 (s, 1H), 8.27 (d, J=5.5 Hz, 1H), 7.47-7.30 (m, 4H),7.21-7.05 (m, 5H), 6.13 (d, J=5.5 Hz, 1H), 3.73 (dd, J=12.1, 5.8 Hz,2H), 3.69-3.57 (m, 3H), 3.55-3.43 (m, 1H), 1.41 (t, J=4.6 Hz, 9H).

Example 626:(R)-5-(4-Cyclobutoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using methods analogous to Method 1,Steps C-H in Example 1, using 4-cyclobutoxyaniline in step A, andtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate. MS (ESI): mass calcd.for C₂₄H₂₅N₅O₃S, 463.6; m/z found, 464.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.33 (d, J=5.56 Hz, 1H), 7.26-7.32 (m, 2H), 7.03 (d, J=9.09Hz, 2H), 6.16 (d, J=5.56 Hz, 1H), 4.77 (quin, J=7.07 Hz, 1H), 4.21-4.31(m, 1H), 3.53 (dd, J=3.79, 11.87 Hz, 1H), 3.33-3.40 (m, 1H), 2.87-3.00(m, 2H), 2.46-2.57 (m, 2H), 2.02-2.23 (m, 4H), 1.67-1.94 (m, 4H).

Example 627: tert-Butyl4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a dry flask at 0° C. containing 4-amino-1-Boc-piperidine (1.62 g,7.82 mmol), diisopropylethylamine (3.74 mL, 21.3 mmol), and THF (28 mL)was added dropwise4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride (Intermediate 40) (3.00 g, 7.11 mmol). The reaction wasmonitored by LCMS. When the reaction had gone to completion, thereaction was quenched saturated NaHCO₃, extracted with DCM, andconcentrated to dryness. The residue was purified by normal phase flashcolumn chromatography (SiO₂) to give the title compound (3800 mg, 91.2%yield) as an off white solid. MS (ESI): mass calcd. for C₃₁H₃₁N₅O₅S,585.7; m/z found, 585.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.46 (s, 1H),8.35 (d, J=5.4 Hz, 1H), 7.45-7.35 (m, 2H), 7.28 (d, J=8.7 Hz, 2H),7.23-7.07 (m, 5H), 6.15 (dd, J=5.7, 1.9 Hz, 1H), 5.55 (d, J=7.8 Hz, 1H),4.10 (qt, J=12.0, 8.2, 7.3 Hz, 3H), 2.90 (t, J=12.7 Hz, 2H), 2.07-1.97(m, 2H), 1.47 (s, 11H).

Example 628: (R)-tert-Butyl3-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared using analogous conditions as found inExample 627 using (R)-1-Boc-3-aminopiperidine step G. MS (ESI): masscalcd. for C₃₁H₃₁N₅O₅S, 585.7; m/z found, 586.0 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): δ 9.48 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 7.44-7.36 (m, 2H), 7.29(dd, J=6.6, 2.7 Hz, 2H), 7.22-7.07 (m, 5H), 6.15 (d, J=5.5 Hz, 1H), 4.11(p, J=6.6, 6.1 Hz, 2H), 3.63 (s, 1H), 3.46 (s, 2H), 3.39 (s, 1H), 2.04(s, 1H), 1.73 (dq, J=12.7, 6.1 Hz, 1H), 1.59 (dt, J=13.5, 6.6 Hz, 1H),1.50 (s, 9H), 1.26 (t, J=7.2 Hz, 1H).

Example 629:(R)-5-(3-Cyclohexylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Method 1,steps F-H using methyl5-(3-cyclohexylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(synthesized as in Example 519, Step B) and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in step G. MS (ESI): mass calcd.for C₂₆H₂₉N₅O₂S, 475.6; m/z found, 476.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.53 (s, 1H), 8.32 (d, J=5.5 Hz, 1H), 7.59-7.51 (m, 1H),7.47-7.41 (m, 1H), 7.33-7.30 (m, 1H), 7.28-7.22 (m, 1H), 6.07 (d, J=5.6Hz, 1H), 4.36-4.24 (m, 1H), 3.48-3.40 (m, 1H), 3.28-3.23 (m, 1H),2.99-2.87 (m, 2H), 2.69-2.62 (m, 1H), 2.09-1.98 (m, 2H), 1.97-1.82 m,5H), 1.81-1.74 (m, 2H), 1.57-1.41 (m, 4H), 1.38-1.26 (m, 1H).

Example 630:(R)-5-(3-Isopropylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using procedures analogous to Method 1,steps E-G in Example 1 using methyl3-amino-4-((3-isopropylphenyl)amino)thieno[2,3-b]pyridine-2-carboxylate(as prepared in Example 529, Step A) and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in step G. MS (ESI): mass calcd.for C₂₃H₂₅N₅O₂S, 435.5; m/z found, 436.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.45 (s, 1H), 8.32-8.29 (m, 1H), 7.59-7.49 (m, 1H), 7.46-7.40(m, 1H), 7.32-7.27 (m, 1H), 7.24-7.18 (m, 1H), 6.12-6.06 (m, 1H),4.34-4.19 (m, 1H), 3.54-3.45 (m, 1H), 3.36-3.31 (m, 1H), 3.06-2.85 (m,3H), 2.17-1.99 (m, 2H), 1.88-1.69 (m, 2H), 1.31-1.25 (m, 6H).

Example 631:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(pyridin-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 3-(pyridin-4-yl)aniline in Step C and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₈H₂₄N₆O₃S, 524.6; m/z found, 525.5 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 10.27-10.07 (m, 1H), 8.67-8.58 (m, 2H), 8.34-8.22 (m,1H), 8.18-8.02 (m, 1H), 8.00-7.88 (m, 2H), 7.79-7.68 (m, 3H), 7.59-7.46(m, 1H), 6.85-6.63 (m, 1H), 6.14-5.99 (m, 2H), 5.74-5.55 (m, 1H),4.47-4.12 (m, 1H), 4.07-3.88 (m, 1H), 3.85-3.65 (m, 1H), 3.11-2.91 (m,1H), 2.80-2.63 (m, 1H), 1.96-1.72 (m, 2H), 1.72-1.54 (m, 1H), 1.47-1.34(m, 1H).

Example 632:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(oxetan-3-yl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 3-(Oxetan-3-yl)aniline

To a round bottom flask were added 3-aminophenylboronic acid pinacolester (12.28 g, 54.36 mmol), nickel(II) iodide (849 mg, 2.72 mmol),trans-2-aminocyclohexanol hydrochloride (412 mg, 2.72 mmol), sodiumbis(trimethylsilyl)amide (9.967 g, 54.36 mmol), and a suspension of3-iodooxetane (5.00 g, 27.2 mmol) in iPrOH (54 mL). The reaction waspurged with N₂ for 30 min while stirring at rt, then purged with N₂ foran additional 15 min while ramping up to 120° C. The reaction wasstirred at 120° C. for 3 h. The reaction was allowed to cool, quenchedwith water, extracted with EtOAc and brine, the organic layer collected,and the aqueous phase extracted again with EtOAc. The combined organiclayers were dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was purified by flash column chromatography to givethe title compound as a brown oil (3.24 g, 79.9% yield).

Step B:5-(3-(Oxetan-3-yl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The title compound was prepared by methods analogous to Method 1, StepsC-F using 3-(oxetan-3-yl)aniline in Step C_(908 mg, 32.6% yield).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(oxetan-3-yl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of5-(3-(oxetan-3-yl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (150 mg, 0.408 mmol), 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one(Intermediate 15) (189 mg, 1.23 mmol), THF (2 mL), anddiisopropylethylamine (0.352 mL, 2.04 mmol) with stirred was added1-propanephosphonic anhydride (0.408 mL, 0.612 mmol) and was stirredovernight at rt. To the reaction mixture was added EtOAc and H₂O, theorganic phase collected, and the H₂O extracted again with EtOAc. Thecombined organics were washed with H₂O and brine, dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby flash column chromatography, then by reverse phase HPLC to give thetitle compound as a white solid (39.9 mg, 19.4% yield). MS (ESI): masscalcd. for C₂₆H₂₅N₅O₄S, 503.6; m/z found, 504.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD): δ 8.28 (d, J=5.6 Hz, 1H), 7.63 (d, J=5.0 Hz, 2H), 7.53 (s, 1H),7.40-7.33 (m, 1H), 6.85-6.74 (m, 1H), 6.20 (dd, J=16.7, 7.6 Hz, 1H),6.11 (d, J=5.6 Hz, 1H), 5.73 (dd, J=20.4, 10.8 Hz, 1H), 5.14-5.08 (m,2H), 4.82-4.76 (m, 2H), 4.58-4.50 (m, 1H), 4.41-4.34 (m, 1H), 4.34-4.28(m, OH), 4.20 (d, J=11.3 Hz, 1H), 4.04-3.91 (m, 1H), 3.21-3.14 (m, 1H),2.89 (q, J=11.9 Hz, 1H), 2.11-2.04 (m, 1H), 1.91-1.83 (m, 1H), 1.80-1.67(m, 1H), 1.65-1.53 (m, 1H).

Example 633:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropoxy-3-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-C, and using 4-isopropoxy-3-methyl-aniline in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₂₇H₂₉N₅O₄S,519.6; m/z found, 520.2 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆): δ 10.18-9.96(d, J=16.7 Hz, 1H), 8.33-8.29 (d, J=5.5 Hz, 1H), 8.11-7.91 (m, 1H),7.22-7.17 (m, 2H), 7.14-7.09 (m, 1H), 6.84-6.70 (m, 1H), 6.14-6.07 (d,J=16.6 Hz, 1H), 6.06-6.00 (d, J=5.5 Hz, 1H), 5.71-5.64 (m, 1H),4.72-4.60 (m, 1H), 4.50-4.15 (m, 1H), 4.10-3.93 (m, 1H), 3.84-3.72 (m,1H), 3.16-2.93 (m, 1H), 2.83-2.63 (m, 1H), 2.20-2.13 (s, 3H), 2.00-1.90(m, 1H), 1.83-1.76 (m, 1H), 1.73-1.59 (m, 1H), 1.50-1.38 (m, 1H),1.36-1.30 (m, 6H).

Example 634:(R)-5-(2-Cyclobutylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-B, and using 2-cyclobutylpyridin-4-amine in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₂₃H₂₄N₆O₂S,448.5; m/z found, 449.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.72-8.66 (d,J=5.2 Hz, 1H), 8.21-8.14 (d, J=5.6 Hz, 1H), 7.45-7.38 (d, J=1.9 Hz, 1H),7.36-7.30 (dd, J=5.3, 1.9 Hz, 1H), 6.12-6.07 (d, J=5.6 Hz, 1H),4.22-4.13 (m, 1H), 3.85-3.74 (m, 1H), 3.40-3.33 (m, 1H), 3.20-3.09 (m,1H), 2.97-2.82 (m, 2H), 2.47-2.32 (m, 4H), 2.18-1.89 (m, 4H), 1.82-1.68(m, 2H).

Example 635:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-C, and using 6-phenoxypyridin-2-amine in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₄S,540.6; m/z found, 541.0 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD): δ 8.34-8.24 (m,1H), 8.11-8.04 (m, 1H), 7.40-7.34 (m, 2H), 7.32-7.27 (d, J=7.4 Hz, 1H),7.20-7.12 (m, 4H), 6.83-6.73 (m, 1H), 6.29-6.23 (d, J=5.5 Hz, 1H),6.23-6.16 (m, 1H), 5.77-5.69 (m, 1H), 4.55-4.24 (m, 1H), 4.20-3.91 (m,2H), 3.23-3.12 (m, 1H), 2.97-2.85 (m, 1H), 2.12-2.01 (d, J=12.3 Hz, 1H),1.91-1.82 (m, 1H), 1.80-1.65 (m, 1H), 1.64-1.52 (m, 1H).

Example 636:(R)-5-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-B, and using 2,2-difluoro-5-aminobenzodioxole in place of3-cyclobutylaniline in step A, and using TFA, DCM, and DCE in place of 4M HCl and dioxane in step B. MS (ESI): mass calcd. for C₂₁H₁₇F₂N₅O₄S,473.5; m/z found, 474.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.29 (d,J=5.6 Hz, 1H), 7.46-7.39 (m, 2H), 7.31-7.24 (m, 1H), 6.17 (d, J=5.6 Hz,1H), 4.28-4.20 (m, 1H), 3.49-3.43 (m, 1H), 3.30-3.25 (m, 1H), 2.97-2.90(m, 2H), 2.11-2.02 (m, 2H), 1.87-1.70 (m, 2H).

Example 637:(R)-5-(3-Isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-B, and using 3-isopropoxyaniline in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₂₃H₂₅N₅O₃S,451.5; m/z found, 452.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): δ 8.62-8.50(d, J=6.1 Hz, 1H), 8.19-8.10 (d, J=5.5 Hz, 1H), 7.46-7.39 (m, 1H),7.03-6.98 (m, 1H), 6.90-6.82 (m, 2H), 5.89-5.83 (d, J=5.5 Hz, 1H),4.67-4.57 (m, 1H), 4.06-3.95 (m, 1H), 3.27-3.20 (m, 2H), 3.09-3.01 (m,1H), 2.77-2.61 (m, 2H), 1.98-1.89 (m, 1H), 1.85-1.76 (m, 1H), 1.66-1.49(m, 2H), 1.28 (d, 6H).

Example 638:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(tert-buty)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-C, and using 3-(tert-butyl)aniline in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₂₇H₂₉N₅O₃S,503.6; m/z found, 504.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.27 (d,J=5.6 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.50 (s,1H), 7.24 (d, J=7.7 Hz, 1H), 6.86-6.74 (m, 1H), 6.20 (dd, J=16.8, 7.3Hz, 1H), 6.06 (d, J=5.6 Hz, 1H), 5.73 (dd, J=18.1, 10.9 Hz, 1H),4.59-4.28 (m, 1H), 4.23-3.93 (m, 2H), 3.22-3.10 (m, 1H), 2.89 (q, J=11.1Hz, 1H), 2.12-2.03 (m, 1H), 1.90-1.83 (m, 1H), 1.80-1.66 (m, 1H),1.66-1.52 (m, 1H), 1.37 (s, 9H).

Example 639: (3S,4S)-tert-Butyl3-methoxy-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidine-1-carboxylate

The title compound was prepared in a manner analogous to Method 1, StepG in Example 1, using4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 58) and using tert-butyl(3S,4S)-3-amino-4-methoxy-pyrrolidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G.MS (ESI): mass calcd. for C₃₁H₃₁N₅O₆S, 601.7; m/z found, 602.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): δ 9.52 (s, 1H), 8.31 (d, J=5.5 Hz, 1H),7.43-7.28 (m, 4H), 7.22-7.07 (m, 6H), 6.56 (s, 1H), 6.14 (d, J=5.5 Hz,1H), 4.52 (tt, J=6.2, 2.6 Hz, 1H), 3.92 (dd, J=10.1, 5.1 Hz, 1H), 3.73(dd, J=11.9, 6.0 Hz, 1H), 3.60 (dd, J=12.4, 4.9 Hz, 1H), 3.53-3.43 (m,4H), 1.38 (m, 9H).

Example 640:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(5-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-C, and using 5-isopropoxy-2-methyl-aniline in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₂₇H₂₉N₅O₄S,519.6; m/z found, 520.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD): δ 8.34-8.28 (d,J=5.6 Hz, 1H), 7.37-7.31 (d, J=8.5 Hz, 1H), 7.04-6.99 (m, 1H), 6.96-6.91(d, J=2.8 Hz, 1H), 6.84-6.74 (m, 1H), 6.25-6.16 (m, 1H), 6.05-6.01 (m,1H), 5.77-5.70 (m, 1H), 4.63-4.56 (m, 1H), 4.55-4.26 (m, 1H), 4.22-3.92(m, 2H), 3.23-3.14 (m, 1H), 2.99-2.85 (m, 1H), 2.11-2.05 (s, 4H),1.92-1.83 (m, 1H), 1.81-1.68 (m, 1H), 1.65-1.49 (m, 1H), 1.32-1.29 (s,6H).

Example 641:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(tert-butylsulfonyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-C, and using 4-(tert-butylsulfonyl)aniline in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₂₇H₂₉N₅O₅S₂,567.7; m/z found, 568.0 [M+H]+. ¹H NMR (400 MHz, CDCl₃): δ 9.51 (s, 1H),8.38 (d, J=5.3 Hz, 1H), 8.11 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H),6.69-6.56 (m, 1H), 6.50-6.38 (m, 0.5H), 6.35 (s, 1H), 6.08 (d, J=4.8 Hz,1H), 5.76 (s, 1H), 5.58 (s, 0.5H), 4.21-3.31 (m, 5H), 2.18-1.70 (m, 4H),1.42 (s, 9H).

Example 642:(R)-5-(4-Hydroxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-B, and using 4-(tert-butoxy)aniline in place of3-cyclobutylaniline in step A, and using TFA and dichloroethane in placeof 4 M HCl and dioxane in step B. MS (ESI): mass calcd. for C₂₀H₁₉N₅O₃S,409.5; m/z found, 410.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d,J=5.6 Hz, 1H), 7.22 (d, J=8.7 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 6.17 (d,J=5.6 Hz, 1H), 4.32-4.19 (m, 1H), 3.53 (dd, J=12.1, 3.8 Hz, 1H), 3.36(d, J=12.7 Hz, 1H), 3.01-2.90 (m, 2H), 2.16-2.02 (m, 2H), 1.94-1.67 (m,2H).

Example 643:(R)-5-(3-Acetylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-B, and using 1-(3-aminophenyl)ethanone in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₂₂H₂₁N₅O₃S,435.5; m/z found, 436.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): δ 10.37-10.27(s, 1H), 9.45-9.31 (m, 1H), 9.26-9.06 (m, 1H), 8.44-8.31 (m, 2H),8.19-8.11 (m, 1H), 8.10-8.03 (s, 1H), 7.83-7.74 (m, 2H), 6.10-5.99 (d,J=5.6 Hz, 1H), 4.29-4.16 (m, 1H), 3.35-3.26 (d, J=11.5 Hz, 1H),3.23-3.13 (d, J=12.2 Hz, 1H), 2.96-2.76 (m, 2H), 2.65-2.58 (s, 3H),1.97-1.86 (m, 2H), 1.80-1.59 (m, 2H).

Example 644:(R)-5-(5-Isopropoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-B, and using 5-isopropoxy-2-methyl-aniline in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₂₄H₂₇N₅O₃S,465.6; m/z found, 466.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD): δ 8.52-8.47 (d,J=6.4 Hz, 1H), 7.41-7.36 (d, J=8.6 Hz, 1H), 7.09-7.04 (dd, J=8.6, 2.6Hz, 1H), 6.97-6.94 (m, 1H), 6.34-6.28 (d, J=6.4 Hz, 1H), 4.65-4.54 (dt,J=12.1, 6.0 Hz, 1H), 4.35-4.26 (m, 1H), 3.57-3.52 (m, 1H), 3.40-3.33 (m,1H), 3.05-2.97 (m, 2H), 2.14-2.06 (m, 5H), 1.92-1.75 (m, 2H), 1.34-1.28(dd, J=6.0, 4.5 Hz, 6H).

Example 645:(R)-4-Oxo-5-(6-phenoxypyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-B, and using 6-phenoxypyridin-2-amine in place of3-cyclobutylaniline in step A.MS (ESI): mass calcd. for C₂₅H₂₂N₆O₃S,486.6; m/z found, 487.0 [M+H]⁺. 1H NMR (600 MHz, MeOD) δ 8.19 (d, J=5.6Hz, 1H), 8.09-8.04 (m, 1H), 7.42-7.37 (m, 2H), 7.28-7.23 (m, 1H),7.22-7.16 (m, 3H), 7.09 (d, J=8.3 Hz, 1H), 6.14 (d, J=5.6 Hz, 1H),4.21-4.11 (m, 1H), 3.31-3.28 (m, 1H), 3.15-3.09 (m, 1H), 2.93-2.82 (m,2H), 2.08-1.93 (m, 2H), 1.79-1.70 (m, 2H).

Example 646:(R)-5-(3-(tert-Butyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-B, and using 3-tert-butylaniline in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₂₄H₂₇N₅O₂S,449.6; m/z found, 450.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.44 (d,J=6.3 Hz, 1H), 7.70-7.62 (m, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.51 (t, J=1.9Hz, 1H), 7.30-7.23 (m, 1H), 6.29 (d, J=6.3 Hz, 1H), 4.36-4.24 (m, 1H),3.54 (dd, J=12.2, 4.0 Hz, 1H), 3.36 (d, J=12.7 Hz, 1H), 3.00 (t, J=11.5Hz, 2H), 2.15-2.04 (m, 2H), 1.96-1.71 (m, 2H), 1.37 (s, 9H).

Example 647:(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(pyridin-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 3-(pyridin-4-yl)aniline in Step C and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₅H₂₂N₆O₂S, 470.5; m/z found, 471.3 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.63-8.55 (m, 2H), 8.21 (d, J=5.6 Hz, 1H), 7.97-7.89 (m,1H), 7.87-7.82 (m, 1H), 7.79-7.70 (m, 3H), 7.55-7.48 (m, 1H), 6.10 (d,J=5.6 Hz, 1H), 4.22-4.10 (m, 1H), 3.34-3.31 (m, 1H), 3.18-3.08 (m, 1H),2.92-2.75 (m, 2H), 2.08-1.92 (m, 2H), 1.80-1.65 (m, 2H).

Example 648: (R)-tert-Butyl3-(5-(3-(tert-butyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared using the procedures found in Example534, step A, and using 3-tert-butylaniline in place of3-cyclobutylaniline. MS (ESI): mass calcd. for C₂₉H₃₅N₅O₄S, 549.7; m/zfound, 550.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.29 (d, J=5.6 Hz, 1H),7.64-7.58 (m, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.50-7.46 (m, 1H), 7.23 (d,J=7.6 Hz, 1H), 6.07 (d, J=5.6 Hz, 1H), 4.13-4.05 (m, 1H), 3.97-3.84 (m,2H), 2.87 (t, J=12.4 Hz, 2H), 2.06-2.01 (m, 1H), 1.79 (d, J=13.0 Hz,1H), 1.67-1.49 (m, 2H), 1.46 (s, 9H), 1.37 (s, 9H).

Example 649: (R)-tert-Butyl3-(5-(3-acetylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared using the procedures found in Example534, step A, and using 1-(3-aminophenyl)ethanone in place of3-cyclobutylaniline. MS (ESI): mass calcd. for C₂₇H₂₉N₅O₅S, 535.6; m/zfound, 536.1 [M+H]+. ¹H NMR (500 MHz, CDCl₃): δ 9.56-9.46 (s, 1H),8.40-8.31 (d, J=5.5 Hz, 1H), 8.15-8.07 (m, 1H), 7.98-7.91 (s, 1H),7.76-7.68 (m, 1H), 7.61-7.53 (s, 1H), 6.12-6.02 (d, J=5.5 Hz, 1H),4.17-4.07 (m, 1H), 3.71-3.43 (m, 4H), 3.40-3.22 (m, 1H), 2.68-2.57 (s,3H), 1.96-1.82 (m, 2H), 1.78-1.67 (m, 1H), 1.65-1.56 (m, 1H), 1.54-1.47(s, 9H).

Example 650:(R)-5-(4-(tert-Butylsulfonyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-B, and using 4-(tert-butylsulfonyl)aniline in place of3-cyclobutylaniline in step A. MS (ESI): mass calcd. for C₂₄H₂₇N₅O₄S₂,513.6; m/z found, 514.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): δ 10.36 (s,1H), 9.42-9.29 (m, 1H), 9.21-9.09 (m, 1H), 8.40 (d, J=5.5 Hz, 1H), 8.10(d, J=8.6 Hz, 2H), 7.88-7.80 (m, 2H), 6.20 (d, J=5.6 Hz, 1H), 4.31-4.20(m, 1H), 3.28 (dd, J=59.3, 11.4 Hz, 2H), 2.99-2.80 (m, 2H), 2.00-1.90(m, 2H), 1.83-1.63 (m, 2H), 1.35 (s, 9H).

Example 651: (R)-tert-Butyl3-(5-(4-(tert-butylsulfonyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared using the procedures found in Example534, step A, and using 4-(tert-butylsulfonyl)aniline in place of3-cyclobutylaniline, to yield the title compound. MS (ESI): mass calcd.for C₂₉H₃₅N₅O₆S₂, 613.8; m/z found, 614.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ 9.55 (s, 1H), 8.38 (d, J=5.5 Hz, 1H), 8.11 (d, J=8.7 Hz, 2H),7.58 (d, J=8.4 Hz, 2H), 6.21-5.35 (m, 2H), 4.16-4.09 (m, 1H), 3.70-3.44(m, 3H), 3.34 (s, 1H), 1.89 (s, 2H), 1.79-1.69 (m, 1H), 1.64-1.55 (m,1H), 1.51 (s, 9H), 1.42 (s, 9H).

Example 652: (R)-tert-Butyl3-(5-(4-(tert-butoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared using the procedures found in Example534, step A, and using 4-(tert-butoxy)aniline in place of3-cyclobutylaniline, to yield the title compound. MS (ESI): mass calcd.for C₂₉H₃₅N₅O₅S, 565.7; m/z found, 566.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.31 (d, J=5.6 Hz, 1H), 7.38-7.29 (m, 2H), 7.24-7.19 (m, 2H),6.14 (d, J=5.6 Hz, 1H), 4.08-3.84 (m, 3H), 3.06-2.79 (m, 2H), 2.06-2.00(m, 1H), 1.83-1.74 (m, 1H), 1.68-1.51 (m, 2H), 1.47 (s, 9H), 1.42 (s,9H).

Example 653: (R)-tert-Butyl3-(5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared using the procedures found in Example525, steps A-B, to yield the title compound. MS (ESI): mass calcd. forC₂₆H₂₅F₂N₅O₆S, 573.6; m/z found, 574.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD):δ 8.32 (d, J=5.6 Hz, 1H), 7.47-7.40 (m, 2H), 7.30 (dd, J=8.5, 2.0 Hz,1H), 6.20 (d, J=5.6 Hz, 1H), 4.08-4.02 (m, 1H), 3.97-3.86 (m, 2H),3.03-2.66 (m, 2H), 2.03 (d, J=2.6 Hz, 1H), 1.82-1.74 (m, 1H), 1.66-1.50(m, 2H), 1.46 (s, 9H).

Example 654: (R)-tert-Butyl3-(5-(6-cyclobutoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared using the procedures found in Example534, step A, and using 6-(cyclobutoxy)pyridin-3-amine in place of3-cyclobutylaniline, to yield the title compound. MS (ESI): mass calcd.for C₂₈H₃₂N₆O₅S, 564.7; m/z found, 565.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.32 (d, J=5.6 Hz, 1H), 8.19 (dd, J=2.7, 0.5 Hz, 1H), 7.74(dd, J=8.8, 2.7 Hz, 1H), 6.95 (dd, J=8.8, 0.5 Hz, 1H), 6.20 (d, J=5.6Hz, 1H), 5.28-5.17 (m, 1H), 4.08-4.02 (m, 1H), 3.97-3.86 (m, 2H),2.99-2.74 (m, 2H), 2.56-2.45 (m, 2H), 2.24-2.11 (m, 2H), 2.07-2.01 (m,1H), 1.94-1.83 (m, 1H), 1.82-1.69 (m, 2H), 1.68-1.51 (m, 2H), 1.46 (s,9H).

Example 655:N-((3R,4R)-1-Acryloyl-4-hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions found inMethod 1, step I in Example 1, and usingN-((3R,4R)-4-Hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 658) in place ofN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.MS (ESI): mass calcd. for C₂₉H₂₅N₅O₅S, 555.6; m/z found, 556.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): δ 9.74 (s, 1H), 8.17 (dd, J=11.1, 5.7 Hz, 1H),7.50 (s, 1H), 7.39 (t, J=7.8 Hz, 2H), 7.28 (d, J=6.9 Hz, 2H), 7.22-7.05(m, 5H), 6.71-6.59 (m, 1H), 6.54 (d, J=11.1 Hz, 1H), 6.26 (d, J=16.8 Hz,1H), 6.00 (t, J=7.4 Hz, 1H), 4.60 (dd, J=27.0, 12.4 Hz, 1H), 3.86 (d,J=14.7 Hz, 3H), 3.48 (s, 1H), 2.86 (t, J=15.9 Hz, 1H), 2.68 (d, J=13.4Hz, 1H), 2.09-2.01 (m, 1H), 1.21 (t, J=7.0 Hz, 1H).

Example 656:(R)-5-(3-Methyl-5-phenoxypyrazin-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-B, and using 3-methyl-5-phenoxy-pyrazin-2-amine(Intermediate 51) in place of 3-cyclobutylaniline in step A, to yieldthe title compound. MS (ESI): mass calcd. for C₂₅H₂₃N₇O₃S, 501.6; m/zfound, 502.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.56-8.50 (m, 1H),8.34-8.27 (s, 1H), 7.51-7.44 (m, 2H), 7.32-7.23 (m, 3H), 6.57-6.52 (d,J=6.3 Hz, 1H), 4.36-4.23 (m, 1H), 3.59-3.50 (d, J=12.7 Hz, 1H),3.40-3.33 (d, J=13.5 Hz, 1H), 3.05-2.93 (m, 2H), 2.36-2.29 (s, 3H),2.18-2.04 (m, 2H), 1.94-1.72 (m, 2H).

Example 657:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-methyl-5-phenoxypyrazin-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the analogous conditions found inMethod 1, step I in Example 1, and using(R)-5-(3-Methyl-5-phenoxypyrazin-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 656) in place ofN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamideto yield the title compound. MS (ESI): mass calcd. for C₂₈H₂₅N₇O₄S,555.6; m/z found, 556.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD): δ 8.37-8.32 (d,J=5.5 Hz, 1H), 8.31-8.26 (s, 1H), 7.50-7.43 (m, 2H), 7.31-7.21 (m, 3H),6.86-6.73 (m, 1H), 6.23-6.15 (m, 2H), 5.78-5.68 (m, 1H), 4.58-4.27 (m,1H), 4.23-3.89 (m, 2H), 3.22-3.11 (m, 1H), 2.96-2.84 (m, 1H), 2.36-2.26(d, J=2.8 Hz, 3H), 2.13-2.01 (m, 1H), 1.91-1.83 (m, 1H), 1.80-1.67 (m,1H), 1.63-1.50 (m, 1H).

Example 658:N-((3R,4R)-4-Hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (3R,4R)-tert-Butyl4-hydroxy-3-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a dry flask were added tert-butyl(3R,4R)-3-amino-4-hydroxypiperidine-1-carboxylate (410 mg, 1.896 mmol),diisopropylethylamine (0.996 mL, 5.69 mmol), and THF (7.6 mL) and wascooled to 0° C.4-Oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride (Intermediate 40, 0.800 g, 1.90 mmol) was added dropwise at 0°C. The reaction was monitored by LCMS and when it had gone tocompletion, the reaction was quenched with saturated NaHCO₃, extractedwith DCM, and concentrated to dryness. The residue was purified bynormal phase flash column chromatography (SiO₂) to give the titlecompound (800 mg, 70% yield). MS (ESI): mass calcd. for C₃₁H₃₁N₅O₆S,601.68; m/z found, 602.2 [M+H]⁺.

Step B:N-((3R,4R)-4-Hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of (3R,4R)-tert-butyl4-hydroxy-3-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(800 mg, 1.33 mmol) in DCM (20 mL) at room temperature was added TFA (22mL) dropwise. The reaction was stirred at room temperature for 30minutes. The reaction was concentrated to dryness and the residue waspurified by normal phase flash column chromatography (SiO₂) to give thetitle compound (660 mg, 99.0% yield) as an off white solid. MS (ESI):mass calcd. for C₂₆H₂₃N₅O₄S, 501.6; m/z found, 502.15 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ 8.25 (dd, J=5.5, 1.7 Hz, 1H), 7.47-7.33 (m, 3H),7.33-7.25 (m, 1H), 7.27-7.09 (m, 5H), 6.12 (dd, J=5.8, 1.9 Hz, 1H), 4.20(d, J=8.2 Hz, 4H), 3.90 (td, J=8.9, 4.2 Hz, 1H), 3.71 (td, J=9.1, 4.2Hz, 1H), 3.32 (dd, J=12.8, 4.3 Hz, 1H), 3.12 (dt, J=13.1, 4.1 Hz, 1H),2.74-2.53 (m, 2H), 2.09 (dq, J=12.6, 3.8 Hz, 1H), 1.60 (dtd, J=13.8,10.3, 3.9 Hz, 1H).

Example 7:N-(cis-3-Hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: cis-tert-Butyl3-hydroxy-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a dry flask were added cis-tert-butyl4-amino-3-hydroxypiperidine-1-carboxylate (402 mg, 1.896 mmol),diisopropylethylamine (0.996 mL, 5.69 mmol), and THF (7.5 mL) and wascooled to 0° C.4-Oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carbonylchloride (Intermediate 40) 0.800 g, 1.90 mmol) was added dropwise at 0°C. The reaction was monitored by LCMS and when it had gone tocompletion, the reaction was quenched with saturated NaHCO₃, extractedwith DCM, and concentrated to dryness. The residue was purified bynormal phase flash column chromatography (SiO₂) to give the titlecompound (950 mg, 83% yield). MS (ESI): mass calcd. for C₃₁H₃₁N₅O₆S,601.68; m/z found, 601.8 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): δ 8.34 (dd,J=5.5, 1.3 Hz, 1H), 7.51-7.42 (m, 4H), 7.26-7.11 (m, 5H), 6.09 (dd,J=5.5, 1.2 Hz, 1H), 5.40 (ddd, J=25.8, 7.8, 5.4 Hz, 1H), 5.00-4.86 (m,2H), 4.37 (d, J=14.2 Hz, 1H), 4.32-4.25 (m, 1H), 4.07-3.97 (m, 1H),3.93-3.79 (m, 3H), 3.63 (dt, J=12.7, 6.6 Hz, 2H), 1.38 (s, 9H).

Step B:N-(Cis-3-hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of cis-tert-butyl3-hydroxy-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(950 mg, 1.58 mmol) in DCM (20 mL) at room temperature was added TFA (26mL) dropwise. The reaction was stirred at room temperature for 30minutes. The reaction was concentrated to dryness and the residue waspurified by normal phase flash column chromatography (SiO₂) to give thetitle compound (750 mg, 94.7% yield) as an off white solid. MS (ESI):mass calcd. for C₂₆H₂₃N₅O₄S, 501.6; m/z found, 502.15 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD): δ 8.29 (d, J=5.6 Hz, 1H), 8.03 (s, 1H), 7.45-7.26 (m,4H), 7.23-7.07 (m, 5H), 6.15 (d, J=5.5 Hz, 1H), 4.27-4.17 (m, 2H), 3.58(s, 1H), 3.45-3.36 (m, 3H), 3.14 (dd, J=13.4, 1.5 Hz, 1H), 3.03 (td,J=13.1, 3.2 Hz, 1H), 2.21 (qd, J=13.3, 4.4 Hz, 1H), 2.00 (bs, 1H), 1.95(ddt, J=13.9, 6.0, 2.7 Hz, 1H).

Example 660:4-Oxo-N-(2-oxopyrrolidin-3-yl)-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using 4-fluoronitrobenzene inplace of 5-fluoro-2-nitrotoluene in step A, and using Pd/C and THF inplace Fe, EtOH/H₂O, and NH₄Cl in step B, and using 4-phenoxyaniline inplace of 2-methyl-4-phenoxyaniline in step C, and using3-aminopyrrolidin-2-one and THF in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and DMF in step G. MS(ESI): mass calcd. for C₂₅H₁₉N₅O₄S, 485.5; m/z found, 486.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.02 (s, 1H), 7.46-7.36 (m, 3H), 7.24-7.08 (m,6H), 6.29-6.00 (m, 4H), 4.71-4.33 (m, 1H), 3.43-3.35 (m, 2H), 2.55-2.44(m, 1H), 2.21-2.19 (m, 1H).

Example 661:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(R)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:2-Chloro-4-((2-methyl-6-phenoxypyridin-3-yl)amino)nicotinonitrile

To a round bottom flask containing2-chloro-4-iodopyridine-3-carbonitrile (72.1 g, 273 mmol) and2-methyl-6-phenoxypyridin-3-amine (Intermediate 49, 50.5 g, 252 mmol)were added Pd(OAc)₂ (1.81 g, 8.06 mmol), followed bybis(2-diphenylphosphinophenyl)ether (DPEphos, 5.66 g, 10.5 mmol), andcesium carbonate (195 g, 598 mmol). The reaction mixture was evacuated,treated with 1,4-dioxane (550 ml) via cannula, vented to N₂, thenstirred at room temperature for 2 h. The reaction mixture wastransferred to a 2 L flask and diluted with water to a total volume of2000 mL. The mixture was stirred for 10 min, then the brown precipitatewas collected by filtration. The solid was under vacuum at 60° C. togive the title compound (94.8 g, 99% yield) as a light orange solid. MS(ESI): mass calcd. for C₁₈H₁₃ClN₄O, 336.08; m/z found, 337.0 [M+H]⁺.

Step B: Methyl5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

To a round bottom flask containing2-chloro-4-((2-methyl-6-phenoxypyridin-3-yl)amino)nicotinonitrile (94.8g, 281 mmol) and dioxane (440 mL) was added cesium carbonate (129 g, 396mmol). The reaction vessel was sealed, evacuated, and vented to N2.Methyl 2-mercaptoacetate (48.0 g, 453 mmol) was added via syringe andthe reaction mixture was heated at 90° C. for 3 h. The reaction mixturewas then treated with solid carbonyl diimidazole (121 g, 746) in smallportions, to control a vigorous release of gas. The reaction was thendiluted with water to a total volume of 2.0 L, and stirred for 10 min.The resulting precipitate was isolated by filtration. The solid wasdissolved in dioxane (600 mL), then treated slowly with water (1.4 L).The resulting suspension was filtered and the solid was dried undervacuum at 80° C. to give the title compound (103 g, 85% yield) as a tansolid. MS (ESI): mass calcd. for C₂₂H₁₆N₄O₄S, 432.09; m/z found, 433.0[M+H]⁺.

Step C:5-(R)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

To a round bottom flask were added methyl5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(52.7 g, 122 mmol), THF (300 mL), MeOH (300 mL), and water (300 mL)followed by lithium hydroxide (24.7 g, 589 mmol). The reaction mixturewas stirred at 55° C. for 3 h. The mixture was transferred to a 2 Lflask and 4 N HCl was added slowly until the solution was neutral. Theresulting suspension was filtered, the filter cake was rinsed withwater, and the solid was dried under vacuum at 60° C. to give the titlecompound (48.3 g, 95%) as a light orange solid. MS (ESI): mass calcd.for C₂₁H₁₄N₄O₄S, 418.07; m/z found, 419.0 [M+H]⁺.

Chiral Separation Method:5-(R)-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid

The atropisomers were chromatographed to isolate the two separateatropisomers, with the respective single atropisomers arbitrarilylabeled as *S or *R to indicate that the compound is a singleatropisomer of unknown absolute configuration. In cases for whichabsolute configuration of a single atropisomeric compound wasdetermined, the atropisomers are named as either S or R throughout (withS corresponding to the alternate designations aS, S_(a), or P; and withR corresponding to the alternate designations aR, R_(a), or M). Thepurification was performed on a chiral SFC column (Stationary phase:Stationary phase: Chiralpak AD-H 5 μm 250×30 mm. The mobile phase was:60% CO₂, 40% MeOH.

Step D: tert-Butyl(R)-3-(5-(*S)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a round bottom flask were added tert-butyl(R)-3-aminopiperidine-1-carboxylate (3.54 g, 17.7 mmol) and DMF (30 mL),followed by5-(R)—(*S)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (3.70 g, 8.83 mmol) and DIPEA (3.75 mL, 21.8 mmol). The reactionmixture was stirred until it became homogeneous, then cooled to 0° C.HATU (5.44 g, 14.3 mmol) was added, the reaction was stirred at 0° C.for 5 min then the mixture was allowed to warm to room temperature over30 min with continuous stirring. An additional portion of HATU (590 mg,1.55 mmol) was added, and the reaction mixture was stirred at roomtemperature for an additional 5 min. Water (12 mL) was added, themixture was cooled at 0° C. for 10 minutes, the precipitate wascollected by filtration and dried under vacuum. The residue was purified(FCC, 50-100% EtOAc/hexanes) to yield the title compound (4.19 g, 79%)as a yellow film. MS (ESI): mass calcd. for C₃₁H₃₂N₆O₅S, 600.22; m/zfound, 601.1 [M+H]⁺.

Step E:(R)-5-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide-2HCl

A flask containing tert-butyl(R)-3-(5-(*S)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(4.18 g, 6.96 mmol) was treated with dioxane (40 mL) followed by 4 NHCl-dioxane (20 ml). The reaction was stirred at room temperature for 1h. Et₂O (150 mL) was added, then the resulting solid was isolated byfiltration. The solid was dried under vacuum to give the title compound(4.68 g, 97%) as a white solid. MS (ESI): mass calcd. for C₂₆H₂₄N₆O₃S,500.16; m/z found, 501.1 [M+H]⁺.

Step F:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(R)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added(R)-5-(*S)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide-2HCl (4.18 g, 7.29 mol), DIEPA (5.0 mL, 29 mmol), and DCM (70 mL). Thereaction mixture was cooled at 0° C., and acrylic anhydride (0.936 mL,8.12 mmol) was added in three portions. The reaction mixture was stirredat 0° C. for 5 min, then saturated aqueous sodium bicarbonate (100 mL)was added followed by DCM (100 mL). The mixture was stirred vigorouslyfor 10 min, then the DCM layer was separated. The aqueous layer wasextracted again with DCM (50 mL). The organic layers were dried (Na₂SO₄)and purified (FCC, SiO₂, isocratic EtOAc). The fractions containingproduct were combined and concentrated to give the title compound (2.14g, 53%) as a white solid. Absolute stereochemical configuration of thetitle compound was confirmed via X-ray analysis after cocrystallizationwith BTK protein. MS (ESI): mass calcd. for C₂₉H₂₆N₆O₄S, 554.17; m/zfound, 555.0 [M+H]⁺. ¹H NMR (600 MHz, MeOD) δ 8.34 (d, J=5.5 Hz, 1H),7.81 (d, J=8.6 Hz, 1H), 7.47-7.41 (m, 2H), 7.28-7.23 (m, 1H), 7.21-7.16(m, 2H), 6.90 (d, J=8.6 Hz, 1H), 6.83-6.74 (m, 1H), 6.23-6.17 (m, 1H),6.13 (d, J=5.5 Hz, 1H), 5.77-5.69 (m, 1H), 4.58-4.27 (m, 1H), 4.22-3.97(m, 1H), 3.95-3.86 (m, 1H), 3.20-3.12 (m, 1H), 2.96-2.80 (m, 1H), 2.24(s, 3H), 2.10-2.02 (m, 1H), 1.92-1.84 (m, 1H), 1.80-1.66 (m, 1H),1.63-1.52 (m, 1H).

Example 662:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:2-Chloro-4-((4-methyl-6-phenoxypyridin-3-yl)amino)nicotinonitrile

To a round bottom flask containing a stir bar and2-chloro-4-iodonicotinonitrile (55.6 g, 210 mmol) and4-methyl-6-phenoxypyridin-3-amine (40.0 g, 200 mmol) were added DPEPhos(4.53 g, 8.41 mmol), Pd(OAc)₂ (1.42 g, 6.31 mmol), and Cs₂CO₃ (147.1 g,451.4 mmol). The vial was evacuated, treated with dioxane (400 mL) viacannula, then vented to nitrogen. The reaction mixture was heated at 90°C. for 60 minutes. The reaction mixture was cooled on an ice bath untilit was near room temperature, then it was transferred to a 2 L flask anddiluted to a total volume of 2100 mL with water. The mixture was stirredfor 10 min and the brown precipitate was collected by filtration. Thefilter cake was dried by pulling air through the frit for 10 min, thendissolved in DCM (400 mL), and dried over anhydrous MgSO₄, filtered, andthe solid rinsed with DCM (100 mL). The DCM solution was evaporated toabout 300 mL and then treated with hexanes (700 mL). The resultingsuspension was stirred for 10 minutes and filtered to give the titlecompound (64.29 g, 90.78% yield) as a brown solid.

Step B: Methyl5-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

A sealed 200 mL round bottom flask containing2-chloro-4-((4-methyl-6-phenoxypyridin-3-yl)amino)nicotinonitrile (3.70g, 11.0 mmol), dioxane (40 mL), and Cs₂CO₃ (10.4 mg, 0.0319 mmol) wasevacuated and vented to N₂, then treated with methyl 2-sulfanylacetate(3.30 g, 31.1 mmol) via syringe. The reaction mixture was heated at 100°C. for 3 h. The reaction mixture was treated with solid CDI (9.18 g,56.6 mmol) in one portion under air, resealed and stirred at rt forovernight. The reaction was diluted with EtOAc (500 mL), DCM (500 mL),and saturated aqueous sodium bicarbonate (150 mL) and the organic phasescollected. The aqueous layer was extracted 2 more times with EtOAc (500mL), and the combined organics were dried over anhydrous MgSO₄,concentrated to dryness, and the residue purified by flash columnchromatography to give the title compound (2.18 g, 45.9% yield).

Step C:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps F-G (including Chiral Separation Method A after step Fto obtain the *S atropisomer) in Example 1, and using Methyl5-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylatein place of Methyl5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylatein step F, and using 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one(Intermediate 15) and diisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and triethylamine instep G, to give the title compound. MS (ESI): mass calcd. forC₂₉H₂₆N₆O₄S, 554.6; m/z found, 555.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.40-8.30 (d, J=5.5 Hz, 1H), 8.15-8.04 (s, 1H), 7.49-7.40 (m, 2H),7.29-7.22 (m, 1H), 7.21-7.15 (m, 2H), 7.08-7.02 (s, 1H), 6.86-6.73 (m,1H), 6.25-6.14 (m, 2H), 5.80-5.69 (m, 1H), 4.57-4.25 (m, 1H), 4.21-3.90(m, 2H), 3.26-3.14 (m, 1H), 3.00-2.84 (m, 1H), 2.24-2.18 (m, 3H),2.12-2.02 (d, J=12.3 Hz, 1H), 1.93-1.83 (m, 1H), 1.81-1.68 (m, 1H),1.65-1.53 (m, 1H).

Example 663:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 662, steps A-C, and using1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate 5) in placeof 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in stepC, to give the title compound. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₄S,540.6; m/z found, 541.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.38-8.33(dd, J=5.5, 1.0 Hz, 1H), 8.12-8.08 (s, 1H), 7.48-7.41 (m, 2H), 7.28-7.22(m, 1H), 7.21-7.16 (m, 2H), 7.07-7.03 (s, 1H), 6.68-6.54 (m, 1H),6.33-6.25 (m, 1H), 6.18-6.15 (dd, J=5.5, 1.0 Hz, 1H), 5.78-5.72 (m, 1H),4.72-4.54 (m, 1H), 4.03-3.48 (m, 4H), 2.41-2.23 (m, 1H), 2.23-2.19 (s,3H), 2.19-2.03 (m, 1H).

Example 664:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(4-methyl-2-phenoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 662, steps A-B, and using 4-methyl-2-phenoxypyrimidin-5-amine inplace of 4-methyl-6-phenoxypyridin-3-amine in step A, and using Method1, steps F-G (including Chiral Resolution Method A after step F toobtain the *S atropisomer) in Example 1, and using methyl5-(4-methyl-2-phenoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylatein place of Methyl5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylatein step F, and using 1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one(Intermediate 5), 1-propanephosphonic anhydride, anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and triethylamine instep G, to give the title compound. MS (ESI): mass calcd. forC₂₇H₂₃N₇O₄S, 541.6; m/z found, 542.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): d8.59-8.48 (d, J=1.1 Hz, 1H), 8.45-8.33 (d, J=5.5 Hz, 1H), 7.51-7.39 (m,2H), 7.34-7.18 (m, 3H), 6.72-6.53 (m, 1H), 6.35-6.22 (m, 2H), 5.81-5.67(m, 1H), 4.73-4.56 (m, 1H), 4.06-3.47 (m, 4H), 2.40-2.02 (m, 5H).

Example 665:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyrimidin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 5-phenoxypyrimidin-2-amine

The title compound was prepared using analogous conditions described inExample 528, Step A, using 5-bromopyrimidin-2-amine in place of5-bromopyrazin-2-amine.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyrimidin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, and C-I in Example 1, using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₇H₂₃N₇O₄S, 541.6; m/z found, 542.2 [M+H]+. ¹H NMR (400 MHz, CD₃OD): d8.73-8.64 (m, 2H), 8.37-8.30 (m, 1H), 7.56-7.44 (m, 2H), 7.34-7.23 (m,3H), 6.86-6.74 (m, 1H), 6.35-6.27 (m, 1H), 6.24-6.14 (m, 1H), 5.79-5.67(m, 1H), 4.57-4.27 (m, 1H), 4.22-3.86 (m, 2H), 3.21-3.10 (m, 1H),2.98-2.82 (m, 1H), 2.12-2.00 (m, 1H), 1.92-1.82 (m, 1H), 1.80-1.65 (m,1H), 1.63-1.52 (m, 1H).

Example 666:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 662, steps A-B, and using 2-methyl-6-phenoxypyridin-3-amine(Intermediate 49) in place of 4-methyl-6-phenoxypyridin-3-amine in stepA, using analogous conditions described in Method 1, steps F-I(including Chiral Resolution Method A after step F to obtain the *Ratropisomer) in Example 1, and using methyl5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylatein place of Methyl5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylatein step F, and using tert-butyl (3R)-3-aminopyrrolidine-1-carboxylateand diisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and triethylamine instep G, to give the title compound. MS (ESI): mass calcd. forC₂₈H₂₄N₆O₄S, 540.6; m/z found, 541.0 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD): d8.39-8.35 (m, 1H), 7.80-7.76 (m, 1H), 7.47-7.42 (m, 2H), 7.27-7.23 (m,1H), 7.21-7.17 (m, 2H), 6.92-6.89 (d, J=8.5 Hz, 1H), 6.67-6.55 (m, 1H),6.33-6.25 (m, 1H), 6.17-6.14 (m, 1H), 5.78-5.73 (m, 1H), 4.70-4.59 (m,1H), 4.04-3.49 (m, 4H), 2.39-2.26 (m, 1H), 2.26-2.22 (s, 3H), 2.19-2.04(m, 1H).

Example 667:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps F-G in Example 1, and using methyl5-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(Example 662, step B) in place of Methyl5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylatein step F, and using 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one(Intermediate 15) and diisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and triethylamine instep G, to give the title compound. MS (ESI): mass calcd. forC₂₉H₂₆N₆O₄S, 554.6; m/z found, 555.0 [M+H]⁺. 1H NMR (400 MHz, MeOD) δ8.40-8.31 (d, J=5.5 Hz, 1H), 8.10 (s, 1H), 7.50-7.41 (m, 2H), 7.30-7.14(m, 3H), 7.05 (s, 1H), 6.88-6.74 (m, 1H), 6.27-6.12 (m, 2H), 5.80-5.67(m, 1H), 4.60-4.25 (m, 1H), 4.22-3.91 (m, 2H), 3.25-3.12 (m, 1H),3.01-2.83 (m, 1H), 2.21 (s, 3H), 2.13-2.01 (m, 1H), 1.94-1.44 (m, 3H).

Example 8:N-(cis-4-Acrylamidotetrahydrofuran-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps F-I in Example 1 (including Chiral Resolution Method Aafter step F to obtain the *S atropisomer), and using methyl5-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(Example 662, step B) in place of Methyl5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylatein step F, and using cis-tetrahydrofuran-3,4-diamine,1-propanephosphonic anhydride, and diisopropylethylamine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G, and using acrylic acid, diisopropylethylamine,and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide inplace of prop-2-enoyl chloride and triethylamine in step I, to give thetitle compound. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₅S, 556.6; m/z found,557.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.39-8.34 (d, J=5.6 Hz, 1H),8.12-8.07 (d, J=2.0 Hz, 1H), 7.48-7.41 (m, 2H), 7.29-7.22 (m, 1H),7.21-7.15 (m, 2H), 7.08-7.02 (s, 1H), 6.34-6.17 (m, 3H), 5.67-5.62 (m,1H), 4.82-4.68 (m, 2H), 4.16-4.05 (m, 2H), 3.85-3.77 (m, 2H), 2.25-2.14(s, 3H).

Example 669:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Example 1,Method 1, Step G, using5-(*S)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 82) and 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one(Intermediate 15). MS (ESI): mass calcd. for C₂₇H₃₀N₆O₃S, 518.6; m/zfound, 519.1 [M+H]⁺. 1H NMR (400 MHz, MeOD) δ 8.42 (s, 1H), 8.34 (d,J=5.5 Hz, 1H), 7.42 (s, 1H), 6.85-6.73 (m, 1H), 6.20 (d, J=15.6 Hz, 1H),6.03 (d, J=5.5 Hz, 1H), 5.80-5.67 (m, 1H), 4.59-4.24 (m, 1H), 4.23-3.89(m, 2H), 3.25-3.12 (m, 1H), 3.00-2.84 (m, 1H), 2.73 (d, J=7.3 Hz, 2H),2.23 (s, 3H), 2.19-2.01 (m, 2H), 1.94-1.84 (m, 1H), 1.81-1.69 (m, 1H),1.65-1.52 (m, 1H), 0.99 (dd, J=6.5, 1.5 Hz, 6H).

Example 670:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 534, steps A-C, and using 2-methyl-6-phenoxypyridin-3-amine(Intermediate 49) in place of 3-cyclobutylaniline in step A, to give thetitle compound. MS (ESI): mass calcd. for C₂₉H₂₆N₆O₄S, 554.6; m/z found,555.1 [M+H]⁺. ¹H NMR (400 MHz, CD3OD): d 8.36 (d, J=5.5 Hz, 1H), 7.80(d, J=8.6 Hz, 1H), 7.48-7.40 (m, 2H), 7.28-7.22 (m, 1H), 7.22-7.16 (m,2H), 6.91 (d, J=8.5 Hz, 1H), 6.85-6.71 (m, 1H), 6.20 (d, J=17.0 Hz, 1H),6.15 (dd, J=5.5, 1.6 Hz, 1H), 5.78-5.68 (m, 1H), 4.58-4.25 (m, 1H),4.21-3.91 (m, 2H), 3.18 (t, J=11.3 Hz, 1H), 2.98-2.83 (m, 1H), 2.25 (s,3H), 2.11-2.03 (m, 1H), 1.91-1.82 (m, 1H), 1.79-1.67 (m, 1H), 1.66-1.51(m, 1H).

Example 671:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Example 1,Method 1, Step G, using5-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 81) and 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one(Intermediate 15). MS (ESI): mass calcd. for C₂₇H₃₀N₆O₃S, 518.6; m/zfound, 519.1 [M+H]⁺. 1H NMR (400 MHz, MeOD) δ 8.43 (s, 1H), 8.37-8.30(d, J=5.5 Hz, 1H), 7.41 (s, 1H), 6.86-6.74 (m, 1H), 6.24-6.16 (m, 1H),6.04 (d, J=5.4 Hz, 1H), 5.80-5.69 (m, 1H), 4.60-4.27 (m, 1H), 4.23-3.92(m, 2H), 3.24-3.13 (m, 1H), 3.00-2.83 (m, 1H), 2.73 (d, J=7.3 Hz, 2H),2.25 (s, 3H), 2.19-2.02 (m, 2H), 1.93-1.84 (m, 1H), 1.81-1.50 (m, 2H),1.05-0.95 (m, 6H).

Example 672:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using2-fluoro-4-methyl-5-nitropyridine and cyclobutanol in place of5-fluoro-2-nitrotoluene and phenol in step A, and using6-cyclobutoxy-4-methylpyridin-3-amine in place of2-methyl-4-phenoxyaniline in step C, and using(R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one (Intermediate 15),diisopropylethylamine, and 1-propanephosphonic anhydride in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G (98 mg, 36% yield). MS (ESI): mass calcd. forC₂₇H₂₈N₆O₄S, 532.6; m/z found, 533.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ8.34 (d, J=5.5 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 6.87-6.73 (m, 2H), 6.20(d, J=16.8 Hz, 1H), 6.11 (d, J=5.5 Hz, 1H), 5.74 (t, J=8.9 Hz, 1H),5.24-5.14 (m, 1H), 4.59-4.48 (m, 0.5H), 4.33-4.14 (m, 1H), 4.04-3.91 (m,1.5H), 3.25-3.14 (m, 1H), 3.02-2.87 (m, 1H), 2.54-2.44 (m, 2H),2.21-2.11 (m, 5H), 2.11-2.04 (m, 1H), 1.92-1.83 (m, 2H), 1.81-1.67 (m,2H), 1.65-1.52 (m, 1H).

Example 673:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2′,3′-difluoro-[1,1-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of5-(3-bromophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 57, 250 mg, 0.641 mmol),1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (intermediate 5, 90.0 mg,0.641 mmol), triethylamine (129 mg, 1.28 mmol), and HATU (268 mg, 0.705mmol) in DMF (4 mL) was stirred at rt for 3 h. Water was added and theprecipitate was collected by filtration to give a pale yellow solid. Amixture of the solid and (2,3-difluorophenyl)boronic acid, Pd(dppf)Cl₂(52 mg, 0.064 mmol), and Na₂CO₃ (136 mg, 1.28 mmol) in dioxane (30 mL)and H₂O (3 mL) was stirred at 110° C. for 2 h. The reaction wasconcentrated to dryness and the residue was purified by flash columnchromatography to give the title compound (102 mg, 28.8% yield) as apale yellow solid. MS (ESI): mass calcd. for C₂₈H₂₁F₂N₅O₃S, 545.6; m/zfound, 546.1 [M+H]+. ¹H NMR (400 MHz, CD₃OD): δ 8.30-8.24 (m, 1H),7.77-7.66 (m, 3H), 7.54-7.47 (m, 1H), 7.36-7.28 (m, 1H), 7.29-7.17 (m,2H), 6.66-6.49 (m, 1H), 6.31-6.19 (m, 1H), 6.19-6.13 (m, 1H), 5.76-5.68(m, 1H), 4.65-4.53 (m, 1H), 4.00-3.46 (m, 4H), 2.36-2.00 (m, 2H).

Example 674:N-((3R,5S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2′,3′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogues conditions as used inExample 673 and using (3R,5S)-tert-butyl3-amino-5-hydroxypiperidine-1-carboxylate (Intermediate 2) in place of1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate 5), andusing Method 1, step I, to give the title compound as a yellow solid. MS(ESI): mass calcd. for C₂₉H₂₃F₂N₅O₄S, 575.6; m/z found, 576.2 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.34-8.25 (m, 1H), 7.80-7.63 (m, 3H), 7.53-7.47(m, 1H), 7.39-7.18 (m, 3H), 6.84-6.66 (m, 1H), 6.26-6.11 (m, 2H),5.76-5.61 (m, 1H), 4.20-4.05 (m, 1H), 4.00-3.48 (m, 5H), 2.24-2.10 (m,1H), 1.91-1.75 (m, 1H).

Example 675:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G (including Chiral Resolution Method A after step F to obtain the *Ratropisomer) in Example 1, and using tetrahydropyran-4-ylmethanesulfonate and 3-methyl-4-nitrophenol in place of4-fluoro-2-methyl-1-nitrobenzene and phenol in step A, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₉H₃₁N₅O₅S, 561.65; m/z found, 562.5 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.31-8.24 (m, 1H), 7.27-7.19 (m, 1H), 7.06-6.92 (m, 2H),6.83-6.70 (m, 1H), 6.25-6.12 (m, 1H), 6.04-5.97 (m, 1H), 5.76-5.65 (m,1H), 4.67-4.56 (m, 1H), 4.33-4.12 (m, 1H), 4.05-3.82 (m, 4H), 3.66-3.53(m, 2H), 3.23-3.07 (m, 1H), 2.95-2.80 (m, 1H), 2.14-1.99 (m, 6H),1.90-1.79 (m, 1H), 1.79-1.65 (m, 3H), 1.63-1.51 (m, 1H)

Example 676:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(3-methyl-2-phenylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-G (including Chiral Resolution Method A after step F to obtain the *Ratropisomer) in Example 1, and using 3-Methyl-2-phenylpyridin-4-amine(Intermediate 48) in place of 2-methyl-4-phenoxyaniline in step C, andusing 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₉H₂₆N₆O₃S, 538.6; m/z found, 539.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.66 (d, J=5.2 Hz, 1H), 8.37 (d, J=5.5 Hz, 1H), 7.57-7.47 (m,6H), 6.88-6.71 (m, 1H), 6.23-6.16 (m, 2H), 5.79-5.68 (m, 1H), 4.61-4.26(m, 1H), 4.19-3.93 (m, 2H), 3.23-3.12 (m, 1H), 2.98-2.83 (m, 1H), 2.16(s, 3H), 2.09-2.02 (m, 1H), 1.90-1.83 (m, 1H), 1.78-1.67 (m, 1H),1.63-1.52 (m, 1H).

Example 677:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-cyclohexylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 2-Cyclohexylpyridin-4-amine

A solution of 2-chloro-4-nitropyridine (2.50 g, 15.8 mmol),cyclohexen-1-ylboronic acid (2.38 g, 18.9 mmol), Pd(dppf)Cl₂ (0.643 g,0.788 mmol), and Na₂CO₃ (3.34 g, 31.5 mmol) in dioxane (50 mL) and H₂O(5 mL) was stirred at 110° C. overnight. The reaction was concentratedto dryness and the residue was purified by flash column chromatographyto give a yellow solid. The yellow solid was dissolved in EtOH (100 mL)at rt and Pd/C (500 mg) was added. The mixture was flushed with H₂ (2×)and was stirred at rt for 16 h. The reaction was filtered andconcentrated to dryness to give the title compound (2.0 g, 72% yield),which was used in the next step without further purification.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-cyclohexylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 2-cyclohexylpyridin-4-amine in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₈H₃₀N₆O₃S, 530.6; m/z found, 531.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.67 (d, J=5.3 Hz, 1H), 8.29 (d, J=5.6 Hz, 1H), 7.55-7.48 (m, 1H),7.45-7.37 (m, 1H), 6.87-6.71 (m, 1H), 6.25-6.12 (m, 2H), 5.77-5.61 (m,1H), 4.58-4.31 (m, 1H), 4.25-3.87 (m, 2H), 3.20-3.07 (m, 1H), 2.90-2.75(m, 2H), 2.07-1.82 (m, 6H), 1.77-1.28 (m, 8H).

Example 678:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenylpyridazin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 6-chloropyridazin-4-amine andphenylboronic acid in place of 2-chloro-4-nitropyridine andcyclohexen-1-ylboronic acid and no Pd/C reduction in step A, and usingMethod 1, steps C-I in Example 1, and using 6-phenylpyridazin-4-amine inplace of 2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₇H₂₃N₇O₃S, 525.6; m/z found, 526.6 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ9.33 (s, 1H), 8.53-8.42 (m, 1H), 8.33 (d, J=5.4 Hz, 1H), 8.21-8.09 (m,2H), 7.57-7.49 (m, 3H), 6.83-6.64 (m, 1H), 6.48-6.36 (m, 1H), 6.18-6.08(m, 1H), 5.75-5.59 (m, 1H), 4.54-4.24 (m, 1H), 4.19-3.84 (m, 2H),3.18-3.04 (m, 1H), 2.93-2.76 (m, 1H), 2.10-1.98 (m, 1H), 1.88-1.76 (m,1H), 1.76-1.61 (m, 1H), 1.56-1.42 (m, 1H).

Example 679:N-((3R,5S)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2′,3′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogues conditions described inExample 673 and using tert-butyl(3R,5S)-3-amino-5-methoxypiperidine-1-carboxylate (Intermediate 29) inplace of 1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate5), and using Method 1, step I, to give the title compound as a yellowsolid. MS (ESI): mass calcd. for C₃₀H₂₅F₂N₅O₄S, 589.6; m/z found, 590.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.25-8.17 (m, 1H), 7.74-7.61 (m, 3H),7.55-7.43 (m, 1H), 7.33-7.13 (m, 3H), 6.83-6.55 (m, 1H), 6.19-5.99 (m,2H), 5.77-5.48 (m, 1H), 4.15-3.99 (m, 2H), 3.89-3.44 (m, 4H), 3.44-3.40(m, 3H), 2.20-2.06 (m, 1H), 1.96-1.81 (m, 1H).

Example 680:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(6-phenoxypyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Method 1,steps A-I in Example 1, and using 2-chloro-5-nitropyridine in place of5-fluoro-2-nitrotoluene in step A, and using Pd/C and MeOH in place ofFe, EtOH/H₂O, and NH₄Cl in step B, and using 6-phenoxypyridin-3-amine inplace of 2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G. MS (ESI):mass calcd. for C₂₇H₂₂N₆O₄S, 526.6; m/z found, 526.9 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): δ 9.58 (s, 1H), 8.33-8.27 (m, 1H), 8.20 (q, J=4.3, 3.5 Hz,1H), 7.79-7.70 (m, 1H), 7.62 (d, J=6.9 Hz, 1H), 7.43 (t, J=7.7 Hz, 2H),7.30-7.17 (m, 3H), 7.10 (dd, J=8.7, 1.9 Hz, 1H), 6.46-6.23 (m, 2H), 6.13(t, J=6.0 Hz, 1H), 5.67 (ddd, J=16.4, 9.2, 3.2 Hz, 1H), 4.68 (dq,J=32.2, 5.1, 4.6 Hz, 1H), 3.82-3.55 (m, 4H), 2.25 (ddt, J=38.8, 13.2,6.1 Hz, 2H).

Example 681:N—((R)-1-((*E)-3-((S)-1-Acetylpyrrolidin-2-yl)-2-cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (S)-1-(2-(Hydroxymethyl)pyrrolidin-1-yl)ethanone

To a solution of (S)-pyrrolidin-2-ylmethanol (0.50 g, 4.9 mmol) in EtOAc(20 mL) was added acetic anhydride (0.555 g, 5.43 mmol) and was stirredunder nitrogen for 18 h. K₂CO₃ (1.364 g, 9.886 mmol) was added andstirring was continued for few minutes. The reaction was filteredthrough celite and the filtrate was concentrated to dryness to give thetitle compound (0.57 g 80% yield) as a white solid. MS (ESI): masscalcd. for C₇H₁₃NO₂, 143.18; m/z found, 144.1 [M+H]+.

Step B: (S)-1-Acetylpyrrolidine-2-carbaldehyde

A solution of oxalyl dichloride (0.683 g, 5.38 mmol) in dry DCM (20 mL)was cooled to −78° C. under a N₂ atmosphere and (methylsulfinyl)methane(0.840 g, 10.8 mmol) was added to the reaction mixture, followed by(S)-1-(2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (0.700 g, 4.89 mmol)and was stirred for 30 minutes at −78° C. Triethylamine (2.473 g, 24.44mmol) was added dropwise and the reaction was allowed to warm up to roomtemperature. After complete consumption of(S)-1-(2-(hydroxymethyl)pyrrolidin-1-yl)ethanone, the reaction wasquenched with distilled water, stirred for 5 minutes and the reactionmixture was extracted DCM. The combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated to dryness to give the title compound(0.590 g, 85.5% yield).

Step C:N—((R)-1-((*E)-3-((S)-1-Acetylpyrrolidin-2-yl)-2-cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 150 mg, 0.265 mmol),(S)-1-acetylpyrrolidine-2-carbaldehyde (112 mg, 0.795 mmol), piperidine(0.30 mL), AcOH (0.10 mL), dioxane (10.0 mL), and 4A molecular sieves(0.50 g) was stirred at 100° C. for 1 h under N2. The reaction wasconcentrated to dryness and purified by normal phase flash columnchromatography (SiO₂) to give the title compound (68 mg, 99% yield) as awhite solid. MS (ESI): mass calcd. for C₃₇H₃₅N₇O₅S, 689.8; m/z found,690.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34-8.29 (m, 1H), 7.42-7.35(m, 2H), 7.33-7.26 (m, 1H), 7.19-7.12 (m, 1H), 7.09-7.02 (m, 3H),7.00-6.93 (m, 1H), 6.92-6.61 (m, 1H), 6.08-6.03 (m, 1H), 4.41-3.48 (m,6H), 3.26-2.81 (m, 2H), 2.28-2.16 (m, 1H), 2.11 (s, 3H), 2.09-1.95 (m,5H), 1.95-1.76 (m, 3H), 1.74-1.53 (m, 2H).

Example 682:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-cyclobutoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G, (including Chiral Resolution Method A after step Fto obtain the *S atropisomer) in Example 1, and using2-fluoro-5-nitro-6-picoline, cyclobutanol, and Cs₂CO₃ in place of5-fluoro-2-nitrotoluene, phenol, and K₂CO₃ in step A, and using Zn inplace of Fe in step B, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15),1-propanephosphonic anhydride, and diisopropylethylamine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G, to give the title compound. MS (ESI): masscalcd. for C₂₇H₂₈N₆O₄S, 532.6; m/z found, 533.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.33 (d, J=5.6 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 6.86-6.72 (m,2H), 6.20 (d, J=16.9 Hz, 1H), 6.08 (d, J=5.6 Hz, 1H), 5.80-5.69 (m, 1H),5.26-5.17 (m, 1H), 4.59-4.25 (m, 1H), 4.21-3.91 (m, 2H), 3.19 (t, J=10.8Hz, 1H), 3.03-2.85 (m, 1H), 2.56-2.44 (m, 2H), 2.25 (s, 3H), 2.23-2.12(m, 2H), 2.12-2.02 (m, 1H), 1.94-1.82 (m, 2H), 1.80-1.67 (m, 2H),1.65-1.51 (m, 1H).

Example 683:N—((R)-1-((E)-3-((R)-1-Acetylpyrrolidin-2-yl)-2-cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-1-Acetylpyrrolidine-2-carbaldehyde

To a solution of oxalyl dichloride (439 mg, 3.46 mmol) in dry DCM (20mL) cooled to −78° C. under a N₂ atmosphere was added(methylsulfinyl)methane (540 mg, 6.91 mmol), followed by(R)-1-(2-(hydroxymethyl)pyrrolidin-1-yl)ethanone (450 mg, 3.14 mmol) andwas stirred for 30 minutes at −78° C. Triethylamine (1.59 g, 15.7 mmol)was added dropwise and the reaction was allowed to warm to roomtemperature. After the complete consumption of(R)-1-(2-(hydroxymethyl)pyrrolidin-1-yl)ethanone, the reaction wasquenched with distilled water, stirred for 5 minutes, and extracted withDCM. The combined organic extracts were dried over anhydrous Na₂SO₄ andconcentrated to dryness to give the title compound (330 mg, 74.4%yield).

Step B:N—((R)-1-((E)-3-((R)-1-Acetylpyrrolidin-2-yl)-2-cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 874, 150 mg, 0.265 mmol),(R)-1-acetylpyrrolidine-2-carbaldehyde (112 mg, 0.795 mmol), piperidine(0.30 mL), AcOH (0.10 mL), dioxane (10.0 mL), and 4A molecular sieves(0.50 g) was stirred at 100° C. for 1 h under N2. The reaction wasconcentrated to dryness and purified by normal phase flash columnchromatography (SiO₂) to give the title compound (48 mg, 26% yield) as awhite solid. MS (ESI): mass calcd. for C₃₇H₃₅N₇O₅S, 689.8; m/z found,690.2 [M+H]+. ¹H NMR (400 MHz, CD₃OD): δ 8.34-8.29 (m, 1H), 7.42-7.35(m, 2H), 7.33-7.26 (m, 1H), 7.19-7.12 (m, 1H), 7.09-7.02 (m, 3H),7.00-6.93 (m, 1H), 6.92-6.61 (m, 1H), 6.08-6.03 (m, 1H), 4.33-3.90 (m,3H), 3.88-3.48 (m, 3H), 3.26-2.81 (m, 2H), 2.28-2.16 (m, 1H), 2.11 (s,3H), 2.09-1.95 (m, 5H), 1.95-1.76 (m, 3H), 1.74-1.53 (m, 2H).

Example 9:5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((E)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: Benzyl 3,4-dihydroxypyrrolidine-1-carboxylate

To a solution of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (5.00 g,24.6 mmol) in THF (40 mL) and water (15 mL) were added OsO₄ (62 mg, 0.25mmol) and N-methylmorpholine N-oxide (3.747 g, 31.98 mmol) and wasstirred at room temperature for 15 h. The reaction mixture wasconcentrated to dryness and the residue was partitioned between EtOAcand water. The organic layer was collected and the aqueous layer wasextracted with EtOAc. The combined organic layers were dried overanhydrous Na₂SO₄, concentrated to dryness, and purified by flash columnchromatography to give the title compound (4.8 g, 82% yield).

Step B: Benzyl(4aR,7aS)-234a,5.7.7a-hexahydro-[1,4]dioxino[2,3-c]pyrrole-6-carboxylate

Benzyl 3,4-dihydroxypyrrolidine-1-carboxylate (4.8 g, 20 mmol), DCM (30mL), and tetrabutylammonium fluoride (2.645 g, 10.12 mmol) were added toa solution of NaOH (9.00 g, 225 mmol) in water (30 mL) and the mixturewas stirred at 55° C. for 48 h. The reaction was extracted with DCM,concentrated to dryness, and purified by flash column chromatography togive the title compound (0.96 g, 18% yield) as a white solid.

Step C: (4aR,7aS)-3,4a,5,6,7,7a-Hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole

A solution of benzyl(4aR,7aS)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrole-6-carboxylate(0.96 g, 3.6 mmol) and Pd(OH)₂ (51 mg, 0.36 mmol) in MeOH (10 mL) wasreacted at rt for 3 h under H₂. The mixture was filtered andconcentrated to dryness to give the title compound (0.43 g, 91% yield)as a light yellow solid.

Step D: Methyl(E)-4-[(4aR,7aS)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrol-6-yl]but-2-enoate

(4aR,7aS)-3,4a,5,6,7,7a-Hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (30 mg,0.23 mmol) was added to a mixture of methyl (E)-4-bromobut-2-enoate (41mg, 0.23 mmol), diisopropylethylamine (30 mg, 0.23 mmol) in THF (10 mL)and stirred at rt for 15 h. The mixture was concentrated to dryness togive the title compound (55 mg), which was used in the next step withoutpurification.

Step E:(E)-4-[(4aR,7aS)-2,3,4a,5.77a-Hexahydro-[1,4]dioxino[2,3-c]pyrrol-6-yl]but-2-enoicacid

Methyl(E)-4-[(4aR,7aS)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrol-6-yl]but-2-enoate(55 mg, 0.24 mmol) in saturated aqueous HCl (4 M, 5 mL) was reacted atreflux for 1 h. The mixture was concentrated to dryness to give thetitle compound (55 mg), which was used in the next step withoutpurification.

Step F:5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((E)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98) (120 mg, 0.24 mmol),(E)-4-[(4aR,7aS)-2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrol-6-yl]but-2-enoicacid (51 mg, 0.24 mmol), HATU (119 mg, 0.312 mmol), in DMF (5 mL) wasstirred at rt for 5 min, then diisopropylethylamine (93 mg, 0.72 mmol)was added portion wise and stirred at rt for 1 h. The reaction mixturewas purified by reverse phase HPLC and by flash column chromatography togive the title compound (29 mg, 18% yield) as a white solid. MS (ESI):mass calcd. for C₃₇H₃₈N₆O₆S, 694.8; m/z found, 695.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): d 8.33-8.29 (m, 1H), 7.43-7.36 (m, 2H), 7.33-7.27 (m, 1H),7.19-7.13 (m, 1H), 7.11-7.02 (m, 3H), 7.00-6.94 (m, 1H), 6.79-6.60 (m,2H), 6.07-6.03 (m, 1H), 4.17-3.89 (m, 5H), 3.81-3.65 (m, 2H), 3.61-3.32(m, 5H), 3.20-3.04 (m, 1H), 2.97-2.87 (m, 2H), 2.87-2.75 (m, 2H), 2.11(s, 3H), 2.08-1.98 (m, 1H), 1.91-1.82 (m, 1H), 1.81-1.67 (m, 1H),1.66-1.54 (m, 1H).

Example 685:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenylpyrimidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 6-chloropyrimidin-4-amine andphenylboronic acid in place of 2-chloro-4-nitropyridine andcyclohexen-1-ylboronic acid and no Pd/C reduction in step A, and usingMethod 1, steps C-I in Example 1, and using 6-phenylpyridazin-4-amine inplace of 2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₇H₂₃N₇O₃S, 525.6; m/z found, 526.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ9.34-9.27 (m, 1H), 8.39-8.35 (m, 1H), 8.26-8.18 (m, 3H), 7.58-7.50 (m,3H), 6.85-6.71 (m, 1H), 6.64-6.58 (m, 1H), 6.26-6.14 (m, 1H), 5.77-5.66(m, 1H), 4.50-3.94 (m, 3H), 3.23-3.13 (m, 1H), 2.99-2.85 (m, 1H),2.13-2.02 (m, 1H), 1.91-1.83 (m, 1H), 1.80-1.68 (m, 1H), 1.63-1.53 (m,1H).

Example 686:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps F-I in Example 1, and using methyl5-(3-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(Intermediate 68) in place of Methyl5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylatein step F, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₉H₂₄ClN₅O₄S, 574.1; m/z found, 574.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.30 (d, J=5.6 Hz, 1H), 7.72-7.65 (m, 1H), 7.44-7.35 (m,3H), 7.22-7.10 (m, 2H), 7.08-7.00 (m, 2H), 6.83-6.70 (m, 1H), 6.25-6.11(m, 2H), 5.78-5.62 (m, 1H), 4.58-4.25 (m, 1H), 4.21-3.81 (m, 2H),3.25-3.03 (m, 1H), 2.93-2.76 (m, 1H), 2.10-1.95 (m, 1H), 1.92-1.79 (m,1H), 1.79-1.64 (m, 1H), 1.61-1.46 (m, 1H).

Example 687:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 534, steps A-C, and using 6-(cyclobutoxy)pyridin-3-amine inplace of 3-cyclobutylaniline in step A, to give the title compound. MS(ESI): mass calcd. for C₂₆H₂₆N₆O₄S, 518.6; m/z found, 519.2 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD): δ 8.32 (d, J=5.6 Hz, 1H), 8.19 (d, J=2.6 Hz, 1H),7.75 (dd, J=8.8, 2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.84-6.74 (m, 1H),6.23-6.16 (m, 2H), 5.73 (t, J=11.4 Hz, 1H), 5.27-5.18 (m, 1H), 4.57-4.28(m, 1H), 4.21-3.92 (m, 2H), 3.22-3.13 (m, 1H), 2.97-2.84 (m, 1H),2.54-2.46 (m, 2H), 2.24-2.12 (m, 2H), 2.07 (d, J=12.6 Hz, 1H), 1.92-1.83(m, 2H), 1.80-1.68 (m, 2H), 1.66-1.52 (m, 1H).

Example 688:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 4-bromo-1-methyl-2-nitrobenzene andphenylboronic acid in place of 2-chloro-4-nitropyridine andcyclohexen-1-ylboronic acid in step A (with no Pd/C reduction step), andusing Method 1, steps B-I in Example 1, and using2-methyl-5-phenylaniline in place of 2-methyl-4-phenoxyaniline in stepC, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₃₀H₂₇N₅O₃S, 537.6; m/z found, 538.4 [M+H]⁺. 1H NMR (400 MHz,CD₃OD): δ 8.32-8.18 (m, 1H), 7.77-7.67 (m, 1H), 7.66-7.58 (m, 3H),7.54-7.48 (m, 1H), 7.43-7.35 (m, 2H), 7.34-7.25 (m, 1H), 6.89-6.60 (m,1H), 6.28-6.10 (m, 1H), 6.06-5.96 (m, 1H), 5.79-5.61 (m, 1H), 4.63-4.22(m, 1H), 4.21-3.84 (m, 2H), 3.22-3.05 (m, 1H), 2.96-2.75 (m, 1H),2.11-2.00 (m, 1H), 1.92-1.77 (m, 1H), 1.75-1.44 (m, 2H).

Example 689:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-isobutylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 1-bromo-3-nitrobenzene andisobutylboronic acid in place of 2-chloro-4-nitropyridine andcyclohexen-1-ylboronic acid and no Pd/C reduction in step A, and usingMethod 1, steps B-I in Example 1, and using Pd/C in place of Fe in stepB, and using 3-isobutylaniline in place of 2-methyl-4-phenoxyaniline instep C, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₇H₂₉N₅O₃S, 503.6; m/z found, 504.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.30-8.23 (m, 1H), 7.53-7.46 (m, 1H), 7.37-7.31 (m, 1H),7.25-7.19 (m, 2H), 6.85-6.73 (m, 1H), 6.23-6.15 (m, 1H), 6.09-6.03 (m,1H), 5.77-5.67 (m, 1H), 4.53-3.94 (m, 3H), 3.23-3.11 (m, 1H), 2.97-2.85(m, 1H), 2.60-2.53 (m, 2H), 2.11-2.02 (m, 1H), 1.94-1.83 (m, 2H),1.77-1.66 (m, 1H), 1.63-1.52 (m, 1H), 0.95-0.90 (m, 6H).

Example 10:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 670) was resolved by chiral SFC (Stationary phase: CHIRALCELOJ-H 5 μm 250×20 mm, Mobile phase: 75% CO₂, 25% MeOH) give the titlecompound. MS (ESI): mass calcd. for C₂₉H₂₆N₆O₄S, 554.6; m/z found, 555.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.36 (d, J=5.5 Hz, 1H), 7.78 (d,J=8.6 Hz, 1H), 7.50-7.39 (m, 2H), 7.30-7.16 (m, 3H), 6.91 (d, J=8.6 Hz,1H), 6.85-6.72 (m, 1H), 6.26-6.12 (m, 2H), 5.79-5.69 (m, 1H), 4.64-4.24(m, 1H), 4.22-3.90 (m, 2H), 3.26-3.09 (m, 1H), 3.03-2.84 (m, 1H), 2.25(s, 3H), 2.13-2.04 (m, 1H), 1.92-1.84 (m, 1H), 1.81-1.68 (m, 1H),1.65-1.54 (m, 1H).

Example 691:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G, (including Chiral Resolution Step A after step F toobtain the *R atropisomer) in Example 1, and using2-fluoro-4-methyl-5-nitropyridine in place of 5-fluoro-2-nitrotoluene instep A, and using Pd/C in place of Fe in step B, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₉H₂₆N₆O₄S, 554.6; m/z found, 555.0 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.39-8.32 (d, J=5.5 Hz, 1H), 8.13-8.08 (s, 1H), 7.50-7.40 (m,2H), 7.29-7.22 (m, 1H), 7.21-7.16 (m, 2H), 7.07-7.02 (s, 1H), 6.86-6.73(m, 1H), 6.26-6.14 (m, 2H), 5.79-5.69 (m, 1H), 4.59-4.26 (m, 1H),4.21-3.92 (m, 2H), 3.25-3.15 (m, 1H), 3.01-2.84 (m, 1H), 2.24-2.18 (s,3H), 2.12-2.02 (m, 1H), 1.93-1.84 (m, 1H), 1.82-1.69 (m, 1H), 1.66-1.52(m, 1H).

Example 692:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-cyclopentylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using cyclopenten-1-ylboronic acid in place ofcyclohexen-1-ylboronic acid and no Pd/C reduction in step A, and usingMethod 1, steps C-I in Example 1, and using 6-cyclopentylpyridin-4-aminein place of 2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₇H₂₈N₆O₃S, 516.6; m/z found, 517.5 [M+H]+. ¹H NMR (400 MHz, CD₃OD): δ8.68 (d, J=5.3 Hz, 1H), 8.28 (d, J=5.6 Hz, 1H), 7.54-7.51 (m, 1H),7.42-7.36 (m, 1H), 6.86-6.69 (m, 1H), 6.25-6.09 (m, 2H), 5.77-5.62 (m,1H), 4.56-4.29 (m, 1H), 4.24-3.86 (m, 2H), 3.29-3.23 (m, 1H), 3.19-3.05(m, 1H), 2.89-2.76 (m, 1H), 2.16-2.00 (m, 3H), 1.91-1.65 (m, 8H),1.60-1.48 (m, 1H).

Example 693:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(cyclopentyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:2-Chloro-4-((4-(cyclopentyloxy)-2-methylphenyl)amino)nicotinonitrile

To a solution of2-chloro-4-((4-hydroxy-2-methylphenyl)amino)nicotinonitrile(Intermediate 14, 500 mg, 1.93 mmol), cyclopentanol (166 mg, 1.93 mmol),and PPh₃ (1.0 g, 3.8 mmol) in THF (10 mL) was added DIAD (3.8 mL, 3.8mmol) at −78° C., and warmed to 80° C. overnight. The reaction wasquenched with H₂O (10 mL), extracted with DCM, dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby flash column chromatography to give the title compound (220 mg, 35%yield) as a yellow solid. MS (ESI): mass calcd. for C₁₈H₁₈ClN₃O, 327.81;m/z found, 328.1 [M+H]⁺.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(cyclopentyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps D-I, in Example 1, and using2-Chloro-4-((4-(cyclopentyloxy)-2-methylphenyl)amino)nicotinonitrile inplace of 2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrilein step D, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₉H₃₁N₅O₄S, 545.7; m/z found, 546.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆ and CD₃OD): δ 8.33 (d, J=5.5 Hz, 1H), 7.26-7.21 (m, 1H),6.99-6.96 (m, 1H), 6.93-6.90 (m, 1H), 6.84-6.75 (m, 1H), 6.21-6.12 (m,1H), 5.99 (d, J=5.5 Hz, 1H), 5.74-5.68 (m, 1H), 4.91-4.86 (m, 1H),4.58-4.31 (m, 1H), 4.17-3.98 (m, 1H), 3.93-3.83 (m, 1H), 3.20-3.04 (m,1H), 2.90-2.72 (m, 1H), 2.10 (s, 3H), 2.04-1.94 (m, 3H), 1.86-1.76 (m,5H), 1.74-1.61 (m, 3H), 1.57-1.45 (m, 1H).

Example 694:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps C-I, in Example 1, and using 4-methoxy-2-methylanilinein place of 2-chloro-4-iodopyridine-3-carbonitrile in step C, and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₅H₂₅N₅O₄S, 491.6; m/z found, 492.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.34-8.24 (m, 1H), 7.29-7.19 (m, 1H), 7.05-6.99 (m, 1H), 6.98-6.91 (m,1H), 6.85-6.72 (m, 1H), 6.27-6.13 (m, 1H), 6.06-5.96 (m, 1H), 5.79-5.68(m, 1H), 4.61-4.26 (m, 1H), 4.20-3.89 (m, 2H), 3.84 (s, 3H), 3.22-3.10(m, 1H), 2.96-2.81 (m, 1H), 2.16-2.00 (m, 4H), 1.92-1.80 (m, 1H),1.79-1.66 (m, 1H), 1.62-1.51 (m, 1H).

Example 695:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(5-methyl-2-phenylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 2-chloro-5-methylpyridin-4-amine, DMAP,acetic anhydride, and phenylboronic acid in place of2-chloro-4-nitropyridine and cyclohexen-1-ylboronic acid and no Pd/Creduction in step A, and using Method 1, steps C-G in Example 1, andusing 5-methyl-2-phenylpyridin-4-amine in place of2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₉H₂₆N₆O₃S, 538.6; m/z found, 539.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.73 (s, 1H), 8.35-8.26 (m, 1H), 8.07-7.95 (m, 3H), 7.49-7.37(m, 3H), 6.83-6.70 (m, 1H), 6.24-6.09 (m, 2H), 5.77-5.62 (m, 1H),4.62-4.26 (m, 1H), 4.22-3.89 (m, 2H), 3.29-3.08 (m, 1H), 2.93-2.79 (m,1H), 2.23 (s, 3H), 2.10-1.99 (m, 1H), 1.88-1.78 (m, 1H), 1.76-1.62 (m,1H), 1.57-1.46 (m, 1H).

Example 696:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(2-isopropoxyethoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G, in Example 1, and using4-fluoro-2-methyl-1-nitrobenzene and 2-isopropoxyethanol in place of5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C in place ofFe in step B, and using 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one(Intermediate 15) in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₉H₃₃N₅O₅S, 563.7; m/z found, 564.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.30 (d, J=5.6 Hz, 1H), 7.27-7.20 (m, 1H), 7.06-7.00 (m, 1H), 7.00-6.93(m, 1H), 6.84-6.73 (m, 1H), 6.28-6.12 (m, 1H), 6.02 (d, J=5.6 Hz, 1H),5.79-5.67 (m, 1H), 4.55-4.27 (m, 1H), 4.17-4.11 (m, 2H), 4.05-3.91 (m,2H), 3.85-3.79 (m, 2H), 3.76-3.69 (m, 1H), 3.22-3.12 (m, 1H), 2.98-2.84(m, 1H), 2.12 (s, 3H), 2.08-2.02 (m, 1H), 1.91-1.83 (m, 1H), 1.78-1.66(m, 1H), 1.64-1.53 (m, 1H), 1.19 (d, J=6.2, 6H).

Example 697:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-isopropylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 2-chloro-4-nitro-pyridine and2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in place of2-chloro-4-nitropyridine and cyclohexen-1-ylboronic acid in step A, andusing Method 1, steps C-I in Example 1, and using2-isopropylpyridin-4-amine in place of 2-methyl-4-phenoxyaniline in stepC, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₅H₂₆N₆O₃S, 490.6; m/z found, 491.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.68 (d, J=4.9 Hz, 1H), 8.26 (d, J=5.4 Hz, 1H), 7.54 (s, 1H),7.43 (d, J=4.9 Hz, 1H), 6.86-6.70 (m, 1H), 6.24-6.06 (m, 2H), 5.76-5.59(m, 1H), 4.59-4.30 (m, 1H), 4.27-3.84 (m, 2H), 3.22-3.04 (m, 2H),2.88-2.74 (m, 1H), 2.11-1.97 (m, 1H), 1.89-1.78 (m, 1H), 1.76-1.64 (m,1H), 1.59-1.47 (m, 1H), 1.34 (d, J=6.7 Hz, 6H).

Example 698:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-I, in Example 1, and using 5-bromo-2-nitropyridine inplace of 5-fluoro-2-nitrotoluene in step A, and using Pd/C in place ofFe in step B, and using tert-butyl (3R)-3-aminopyrrolidine-1-carboxylateand diisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and triethylamine instep G, to give the title compound. MS (ESI): mass calcd. forC₂₇H₂₂N₆O₄S, 526.6; m/z found, 527.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ9.55 (s, 1H), 8.55-8.21 (m, 2H), 7.57-7.36 (m, 4H), 7.30-7.19 (m, 1H),7.17-6.71 (m, 3H), 6.49-6.31 (m, 2H), 6.26-6.17 (m, 1H), 5.77-5.65 (m,1H), 4.80-4.61 (m, 1H), 4.01-3.38 (m, 4H), 2.41-1.94 (m, 2H).

Example 699:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-phenoxypyrazin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A, C-G, in Example 1, and using 5-bromopyrazin-2-aminein place of 5-fluoro-2-nitrotoluene in step A, and using5-phenoxypyrazin-2-amine in place of 2-methyl-4-phenoxyaniline in stepC, and using 1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one(Intermediate 5) and diisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and triethylamine instep G, to give the title compound. MS (ESI): mass calcd. forC₂₆H₂₁N₇O₄S, 527.6; m/z found, 528.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.53-8.47 (m, 1H), 8.39-8.25 (m, 2H), 7.54-7.41 (m, 2H), 7.34-7.19 (m,3H), 6.72-6.52 (m, 1H), 6.35 (d, J=5.6 Hz, 1H), 6.32-6.22 (m, 1H),5.81-5.69 (m, 1H), 4.70-4.60 (m, 1H), 4.02-3.49 (m, 4H), 2.43-2.01 (m,2H).

Example 700:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-cyclobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G, (including Chiral Resolution Method A after step Fto obtain the *R atropisomer), in Example 1, and using2-fluoro-4-methyl-5-nitropyridine, cyclobutanol, and Cs₂CO₃ in place of5-fluoro-2-nitrotoluene, K₂CO₃, and phenol in step A, and using Zn inplace of Fe in step B, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15),1-propanephosphonic anhydride, and diisopropylethylamine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G, to give the title compound. MS (ESI): masscalcd. for C₂₇H₂₈N₆O₄S, 532.6; m/z found, 533.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD): δ 8.34 (d, J=5.6 Hz, 1H), 8.05 (s, 1H), 6.87-6.75 (m, 2H),6.24-6.17 (m, 1H), 6.11 (d, J=5.5 Hz, 1H), 5.74 (t, J=9.3 Hz, 1H),5.23-5.15 (m, 1H), 4.54-4.26 (m, 1H), 4.20-3.92 (m, 2H), 3.23-3.14 (m,1H), 2.99-2.88 (m, 1H), 2.53-2.44 (m, 2H), 2.21-2.12 (m, 5H), 2.11-2.04(m, 1H), 1.92-1.82 (m, 2H), 1.80-1.67 (m, 2H), 1.65-1.54 (m, 1H).

Example 701:(R)-5-([2,3′-Bipyridin]-4-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 2-chloropyridin-4-amine and3-pyridylboronic acid in place of 2-chloro-4-nitropyridine andcyclohexen-1-ylboronic acid and no Pd/C reduction in step A, and usingMethod 1, steps C-G in Example 1, and using 2-(3-pyridyl)pyridin-4-aminein place of 2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₇H₂₃N₇O₃S, 525.6; m/z found, 526.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 9.27-9.23 (m, 1H), 8.95-8.90 (m, 1H), 8.62-8.57 (m, 1H),8.53-8.49 (m, 1H), 8.35-8.30 (m, 1H), 8.23-8.18 (m, 1H), 7.60-7.57 (m,1H), 7.57-7.53 (m, 1H), 6.84-6.70 (m, 1H), 6.35-6.30 (m, 1H), 6.21-6.12(m, 1H), 5.76-5.63 (m, 1H), 4.58-4.25 (m, 1H), 4.22-3.89 (m, 2H),3.20-3.07 (m, 1H), 2.93-2.77 (m, 1H), 2.09-2.02 (m, 1H), 1.88-1.80 (m,1H), 1.77-1.62 (m, 1H), 1.58-1.47 (m, 1H).

Example 702:(R)-5-(*S)-(4-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H, (including Chiral Resolution Method A after step Fto obtain the *S atropisomer), in Example 1, and using2-chloro-4-methyl-5-nitropyridine and Cs₂CO₃ in place of5-fluoro-2-nitrotoluene and K₂CO₃ in step A, and using Pd/C in place ofFe in step B, and using tert-butyl (3R)-3-aminopyrrolidine-1-carboxylateand diisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and triethylamine instep G, to give the title compound. MS (ESI): mass calcd. forC₂₅H₂₂N₆O₃S, 486.6; m/z found, 487.0 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD): δ8.60-8.56 (d, J=6.6 Hz, 1H), 8.22-8.18 (s, 1H), 7.50-7.43 (m, 2H),7.30-7.26 (m, 1H), 7.24-7.19 (m, 2H), 7.13-7.09 (s, 1H), 6.61-6.56 (d,J=6.6 Hz, 1H), 4.68-4.60 (m, 1H), 3.64-3.58 (m, 2H), 3.51-3.44 (m, 1H),3.43-3.35 (m, 1H), 2.49-2.38 (m, 1H), 2.30-2.20 (m, 4H).

Example 703:(R,E)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-I, in Example 1, and using2-chloro-1-fluoro-4-nitrobenzene in place of 5-fluoro-2-nitrotoluene instep A, and using tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, and using (E)-4-(dimethylamino)but-2-enoicacid and HATU in place of prop-2-enoyl chloride in step I, to give thetitle compound. MS (ESI): mass calcd. for C₃₁H₂₉ClN₆O₄S, 617.1; m/zfound, 617.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.21-8.13 (m, 1H),7.60-7.54 (m, 1H), 7.43-7.34 (m, 2H), 7.32-7.25 (m, 1H), 7.19-7.11 (m,2H), 7.09-7.01 (m, 2H), 6.86-6.75 (m, 1H), 6.51-6.40 (m, 1H), 6.10-6.04(m, 1H), 4.67-4.56 (m, 1H), 4.02-3.51 (m, 4H), 3.19-3.13 (m, 2H),2.39-2.28 (m, 1H), 2.28-2.24 (m, 6H), 2.23-2.08 (m, 1H).

Example 704:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G, in Example 1, and using 2-fluoro-5-nitro-6-picolineand cyclobutanol in place of 5-fluoro-2-nitrotoluene and phenol in stepA, and using Zn in place of Fe in step B, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15),1-propanephosphonic anhydride, and diisopropylethylamine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G, to give the title compound. MS (ESI): masscalcd. for C₂₇H₂₈N₆O₄S, 532.6; m/z found, 533.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD): δ 8.34 (d, J=5.5 Hz, 1H), 7.62 (dd, J=8.6, 1.8 Hz, 1H),6.85-6.73 (m, 2H), 6.24-6.16 (m, 1H), 6.09 (d, J=5.5 Hz, 1H), 5.78-5.69(m, 1H), 5.26-5.16 (m, 1H), 4.58-4.25 (m, 1H), 4.21-3.92 (m, 2H),3.24-3.14 (m, 1H), 3.01-2.86 (m, 1H), 2.55-2.45 (m, 2H), 2.25 (s, 3H),2.21-2.12 (m, 2H), 2.11-2.04 (m, 1H), 1.92-1.83 (m, 2H), 1.81-1.68 (m,2H), 1.66-1.54 (m, 1H).

Example 705:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(3-isopropylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps C-I in Example 1, and using 3-isopropylaniline in placeof 2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₅H₂₅N₅O₃S, 475.6; m/z found, 476.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.30-8.26 (m, 1H), 7.55-7.48 (m, 1H), 7.45-7.40 (m, 1H), 7.32-7.28 (m,1H), 7.24-7.18 (m, 1H), 6.68-6.54 (m, 1H), 6.32-6.23 (m, 1H), 6.09-6.03(m, 1H), 5.78-5.70 (m, 1H), 4.69-4.55 (m, 1H), 4.02-3.49 (m, 4H),3.05-2.93 (m, 1H), 2.38-2.01 (m, 2H), 1.29-1.25 (m, 6H).

Example 706:(R)-5-(2′,3′-Difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was synthesized as in Example 498, steps A-D. MS(ESI): mass calcd. for C₂₆H₂₁F₂N₅O₂S, 505.5; m/z found, 506.4 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.53 (br, 1H), 8.29 (d, J=5.6 Hz, 1H), 7.82-7.69(m, 2H), 7.65 (s, 1H), 7.54-7.45 (m, 1H), 7.41-7.17 (m, 3H), 6.18 (d,J=5.5 Hz, 1H), 4.31-4.16 (m, 1H), 3.53-3.43 (m, 1H), 3.28-3.25 (m, 1H),2.97-2.86 (m, 2H), 2.12-1.98 (m, 2H), 1.90-1.67 (m, 2H).

Example 707:N-((1RS,2RS)-2-Aminocyclopentyl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G (including Chiral Resolution Method A after step Fto obtain the *S atropisomer) in Example 1, and using2-chloro-4-methyl-5-nitropyridine and Cs₂CO₃ in place of5-fluoro-2-nitrotoluene and K₂CO₃ in step A, and using Pd/C in place ofFe in step B, and using cis-diaminotetrahydrofuran, 1-propanephosphonicanhydride, and diisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G, to give the title compound. MS (ESI): masscalcd. for C₂₅H₂₂N₆O₄S, 502.6; m/z found, 503.0 [M+H]⁺. ¹H NMR (600 MHz,CD₃OD): δ 8.30-8.27 (m, 1H), 8.09-8.05 (d, J=4.2 Hz, 1H), 7.46-7.41 (m,2H), 7.27-7.22 (m, 1H), 7.21-7.16 (m, 2H), 7.05-7.02 (s, 1H), 6.11-6.04(m, 1H), 4.71-4.63 (m, 1H), 4.15-4.09 (m, 1H), 4.08-4.03 (m, 1H),3.85-3.80 (m, 1H), 3.78-3.73 (m, 1H), 3.72-3.66 (m, 1H), 2.23-2.15 (m,3H).

Example 708:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(tetrahydro-2H-pyran-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-C, and using 3-tetrahydropyran-4-ylaniline (Intermediate47) in place of 3-cyclobutylaniline in step A, to yield the titlecompound. MS (ESI): mass calcd. for C₂₈H₂₉N₅O₄S, 531.6; m/z found, 532.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.29 (d, J=5.6 Hz, 1H), 7.56 (t,J=7.8 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.35 (s, 1H), 7.28 (d, J=7.3 Hz,1H), 6.85-6.75 (m, 1H), 6.20 (dd, J=16.9, 6.2 Hz, 1H), 6.08 (d, J=5.6Hz, 1H), 5.73 (t, J=11.8 Hz, 1H), 4.58-4.27 (m, 1H), 4.22-3.92 (m, 4H),3.61-3.52 (m, 2H), 3.22-3.14 (m, 1H), 2.97-2.86 (m, 2H), 2.12-2.04 (m,1H), 1.91-1.66 (m, 6H), 1.65-1.52 (m, 1H).

Example 709:(R)-5-([2,2′-Bipyridin]-4-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: Methyl5-(2-chloropyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

The title compound was prepared using analogous conditions described inMethod 1, steps C-E in Example 1, and using 2-chloropyridin-4-amine inplace of 2-methyl-4-phenoxyaniline in step C, to give the titlecompound.

Step B: Methyl5-([2,2′-bipyridin]-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate

A solution of trimethyl(2-pyridyl)stannane (0.536 g, 2.22 mmol), Methyl5-(2-chloropyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(0.80 g, 1.1 mmol), and Pd(PPh₃)₄ (0.128 g, 0.111 mmol) in DMF (10 mL)was degassed under N₂ and was stirred at 85° C. for 4 hours. Thereaction was concentrated to dryness and the residue was purified byflash column chromatography to give the title compound (0.50 g, 56%yield) as a yellow solid.

Step C:(R)-5-([2,2′-Bipyridin]-4-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps F-G in Example 1, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₇H₂₃N₇O₃S, 525.6; m/z found, 526.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.94-8.81 (m, 1H), 8.65-8.58 (m, 1H), 8.52-8.44 (m, 1H),8.44-8.36 (m, 1H), 8.32-8.23 (m, 1H), 7.98-7.86 (m, 1H), 7.60-7.51 (m,1H), 7.46-7.38 (m, 1H), 6.87-6.70 (m, 1H), 6.31-6.23 (m, 1H), 6.23-6.12(m, 1H), 5.78-5.66 (m, 1H), 4.57-4.22 (m, 1H), 4.22-3.89 (m, 2H),3.24-3.10 (m, 1H), 2.98-2.84 (m, 1H), 2.12-2.02 (m, 1H), 1.91-1.81 (m,1H), 1.81-1.64 (m, 1H), 1.62-1.51 (m, 1H).

Example 710:(R)-5-(2′,3′-Difluoro-[1,1′-biphenyl]-3-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2′,3′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 706, 100 mg, 0.198 mmol) and formaldehyde (0.5 mL, 37 wt. % inH₂O) in MeOH (5 mL) was added NaBH(AcO)₃ (176 mg, 0.831 mmol) and wasstirred at rt overnight. The reaction was concentrated to dryness andpurified by flash column chromatography to give the title compound as apale yellow solid. MS (ESI): mass calcd. for C₂₇H₂₃F₂N₅O₂S, 519.6; m/zfound, 520.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.47 (s, 1H), 8.28 (d,J=5.6 Hz, 1H), 7.78-7.65 (m, 3H), 7.54-7.47 (m, 1H), 7.38-7.19 (m, 3H),6.17 (d, J=5.6 Hz, 1H), 4.30-4.17 (m, 1H), 3.40-3.31 (m, 1H), 3.18-3.06(m, 1H), 2.74-2.60 (m, 5H), 2.04-1.92 (m, 2H), 1.86-1.72 (m, 1H),1.69-1.56 (m, 1H).

Example 711:(R)-5-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 534, steps A-B, and using 2-methyl-6-phenoxypyridin-3-amine(Intermediate 49) in place of 3-cyclobutylaniline in step A, to give thetitle compound. MS (ESI): mass calcd. for C₂₆H₂₄N₆O₃S, 500.6; m/z found,501.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.58 (d, J=6.5 Hz, 1H), 7.88(d, J=8.7 Hz, 1H), 7.53-7.43 (m, 2H), 7.33-7.26 (m, 1H), 7.25-7.20 (m,2H), 6.98 (d, J=8.6 Hz, 1H), 6.54 (d, J=6.5 Hz, 1H), 4.36-4.26 (m, 1H),3.54 (dd, J=12.1, 3.8 Hz, 1H), 3.40-3.34 (m, 1H), 3.01 (t, J=11.5 Hz,2H), 2.30 (s, 3H), 2.15-2.06 (m, 2H), 1.94-1.73 (m, 2H).

Example 11:N-(trans-1-Acryloyl-3-hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 1, step I, and usingN-(trans-3-Hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 615) in place ofN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.MS (ESI): mass calcd. for C₂₉H₂₅N₅O₅S, 555.6; m/z found, 556.1 [M+H]+.1H NMR (500 MHz, Chloroform-d) δ 8.29 (dq, J=5.4, 1.7 Hz, 1H), 7.46-7.38(m, 2H), 7.38-7.25 (m, 3H), 7.25-7.09 (m, 5H), 6.63 (ddd, J=26.2, 16.2,10.9 Hz, 1H), 6.33-6.24 (m, 1H), 6.24-6.12 (m, 1H), 5.80-5.69 (m, 1H),4.19 (d, J=13.4 Hz, 1H), 4.06-3.98 (m, 1H), 3.50 (s, 1H), 3.44-3.35 (m,1H), 3.20 (t, J=13.0 Hz, 1H), 3.04 (t, J=12.0 Hz, 1H), 2.77 (t, J=13.2Hz, 1H), 2.63 (q, J=16.6, 14.2 Hz, 1H), 2.21 (d, J=13.2 Hz, 1H), 2.09(d, J=12.9 Hz, 1H).

Example 713:(R)-5-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 662, steps A-B, and using 2-methyl-6-phenoxypyridin-3-amine(Intermediate 49) in place of 4-methyl-6-phenoxypyridin-3-amine in stepA, followed by treatment with Chiral Resolution Method A after step F toobtain the *S atropisomer in Example 1, and using methyl5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylatein place of methyl4-[2-methyl-N-(methylcarbamoyl)-4-phenoxyanilino]-3a,4-dihydrothieno[2,3-b]pyridine-2-carboxylatein step F, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and triethylamine instep G. MS (ESI): mass calcd. for C₂₆H₂₄N₆O₃S, 500.6; m/z found, 501.1[M+H]⁺. 1H NMR (400 MHz, MeOD) δ 8.54 (d, J=6.4 Hz, 1H), 7.84 (d, J=8.7Hz, 1H), 7.50-7.43 (m, 2H), 7.31-7.25 (m, 1H), 7.24-7.18 (m, 2H), 6.96(d, J=8.2 Hz, 1H), 6.47 (d, J=6.3 Hz, 1H), 4.36-4.25 (m, 1H), 3.58-3.50(m, 1H), 3.41-3.33 (m, 1H), 3.04-2.93 (m, 2H), 2.28 (s, 3H), 2.15-2.03(m, 2H), 1.92-1.73 (m, 2H).

Example 714:(R)—N-(1-(Methylglycyl)piperidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 662, steps A-B, and using 2-phenylpyridin-4-amine in place of4-methyl-6-phenoxypyridin-3-amine in step A, followed by treatment ofthe product with analogous conditions described in Method 1, steps F-Iin Example 1, and using methyl4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylatein place of methyl4-[2-methyl-N-(methylcarbamoyl)-4-phenoxyanilino]-3a,4-dihydrothieno[2,3-b]pyridine-2-carboxylatein step F, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, and using2-[tert-butoxycarbonyl(methyl)amino]acetic acid (Intermediate 21) andHATU in place of prop-2-enoyl chloride in step I, followed byBoc-deprotection using saturated aqueous HCl and MeOH, to give the titlecompound. MS (ESI): mass calcd. for C₂₈H₂₇N₇O₃S, 541.6; m/z found, 542.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.83-8.76 (m, 1H), 8.12-8.05 (m, 1H),8.04-7.98 (m, 2H), 7.95-7.88 (m, 1H), 7.51-7.43 (m, 3H), 7.42-7.38 (m,1H), 6.13-5.99 (m, 1H), 4.47-3.79 (m, 4H), 3.73-3.44 (m, 2H), 3.24-3.06(m, 1H), 2.67-2.51 (m, 3H), 2.06-1.70 (m, 3H), 1.65-1.54 (m, 1H).

Example 715:(R)-5-(*S)-(4-Methyl-2-phenoxypyrimidin-5-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A, C-H, (including Chiral Resolution Method A after stepF to obtain the *S atropisomer) in Example 1, and using2-chloro-4-methylpyrimidin-5-amine, dimethyl glycine, and Cs₂CO₃ inplace of 5-fluoro-2-nitrotoluene and K₂CO₃ in step A, and no step B, andusing tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and triethylamine instep G, to give the title compound. MS (ESI): mass calcd. forC₂₄H₂₁N₇O₃S, 487.5; m/z found, 488.0 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD): δ8.56-8.54 (s, 1H), 8.54-8.51 (d, J=6.1 Hz, 1H), 7.49-7.44 (m, 2H),7.31-7.27 (m, 1H), 7.27-7.22 (m, 2H), 6.57-6.53 (d, J=6.1 Hz, 1H),4.63-4.56 (m, 1H), 3.64-3.57 (m, 2H), 3.46-3.42 (m, 1H), 3.40-3.35 (m,1H), 2.48-2.40 (m, 1H), 2.36-2.33 (s, 3H), 2.27-2.20 (m, 1H).

Example 716:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-I, (including Chiral Resolution Method A after step Fto obtain the *S atropisomer) in Example 1, and using6-chloro-2-methyl-3-nitropyridine and Cs₂CO₃ in place of5-fluoro-2-nitrotoluene and K₂CO₃ in step A, and using Pd/C in place ofFe in step B, and using tert-butyl (3R)-3-aminopyrrolidine-1-carboxylateand diisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and triethylamine instep G, and using prop-2-enoyl prop-2-enoate, acetonitrile, anddiisopropylethylamine in place of prop-2-enoyl chloride, DCM, andtriethylamine in step I, to give the title compound. MS (ESI): masscalcd. for C₂₈H₂₄N₆O₄S, 540.6; m/z found, 541.0 [M+H]⁺. ¹H NMR (600 MHz,CD₃OD): δ 8.38-8.35 (m, 1H), 7.80-7.76 (m, 1H), 7.48-7.42 (m, 2H),7.27-7.18 (m, 3H), 6.93-6.89 (d, J=8.7 Hz, 1H), 6.67-6.56 (m, 1H),6.32-6.25 (m, 1H), 6.18-6.13 (m, 1H), 5.78-5.72 (m, 1H), 4.70-4.59 (m,1H), 4.03-3.49 (m, 4H), 2.39-2.25 (m, 1H), 2.25-2.23 (d, J=1.7 Hz, 3H),2.19-2.04 (m, 1H).

Example 717:(R)-5-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H, (including Chiral Resolution Method A after step Fto obtain the *S atropisomer) in Example 1, and using6-chloro-2-methyl-3-nitropyridine and Cs₂CO₃ in place of5-fluoro-2-nitrotoluene and K₂CO₃ in step A, and using Pd/C in place ofFe in step B, and using tert-butyl (3R)-3-aminopyrrolidine-1-carboxylateand diisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and triethylamine instep G, to give the title compound. MS (ESI): mass calcd. forC₂₅H₂₂N₆O₃S, 486.6; m/z found, 487.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.55-8.49 (d, J=6.2 Hz, 1H), 7.86-7.81 (d, J=8.7 Hz, 1H), 7.50-7.42 (m,2H), 7.31-7.19 (m, 3H), 6.99-6.93 (d, J=8.6 Hz, 1H), 6.47-6.42 (d, J=6.3Hz, 1H), 4.65-4.55 (m, 1H), 3.65-3.55 (m, 2H), 3.46-3.34 (m, 2H),2.50-2.38 (m, 1H), 2.32-2.17 (m, 4H).

Example 718:N-((3S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 2-chloropyridin-4-amine and phenylboronicacid in place of 2-chloro-4-nitropyridine and cyclohexen-1-ylboronicacid and no Pd/C reduction in step A, and using Method 1, steps C-I inExample 1, and using 2-phenylpyridin-4-amine in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3S,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate (Intermediate 24) inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₇H₂₂N₆O₄S, 526.6; m/z found, 527.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.86 (d, J=5.3 Hz, 1H), 8.38-8.29 (m, 1H), 8.09-8.00 (m, 3H),7.53-7.43 (m, 4H), 6.63-6.52 (m, 1H), 6.33-6.23 (m, 2H), 5.78-5.70 (m,1H), 4.62-4.54 (m, 1H), 4.50-4.39 (m, 1H), 4.05-3.52 (m, 4H).

Example 719:(R)-4-Oxo-5-(5-phenoxypyrimidin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A, C-H, in Example 1, and using5-bromopyrimidin-2-amine, N,N-dimethylglycine, and Cs₂CO₃ in place of5-fluoro-2-nitrotoluene and K₂CO₃ in step A, and no step B, and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₄H₂₁N₇O₃S, 487.5; m/z found, 488.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.71-8.67 (m, 2H), 8.39-8.35 (m, 2H), 7.54-7.46 (m, 2H), 7.34-7.23 (m,3H), 6.35-6.31 (m, 1H), 4.34-4.19 (m, 1H), 3.57-3.46 (m, 1H), 3.36-3.32(m, 1H), 3.02-2.89 (m, 2H), 2.15-1.99 (m, 2H), 1.88-1.66 (m, 2H).

Example 720:(R)-5-(2-Cyclopentylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using cyclopenten-1-ylboronic acid in place ofcyclohexen-1-ylboronic acid in step A, and using Method 1, steps C-H inExample 1, and using 2-cyclopentylpyridin-4-amine in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₄H₂₆N₆O₂S, 462.6; m/z found, 463.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.73-8.66 (m, 1H), 8.39 (s, 1H), 8.34-8.29 (m, 1H), 7.53-7.48 (m, 1H),7.44-7.33 (m, 1H), 6.26-6.15 (m, 1H), 4.32-4.22 (m, 1H), 3.58-3.47 (m,1H), 3.38-3.31 (m, 2H), 3.01-2.90 (m, 2H), 2.18-2.02 (m, 4H), 1.90-1.69(m, 8H).

Example 721:(R)-5-(3-Isobutylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 1-bromo-3-nitrobenzene andisobutylboronic acid in place of 2-chloro-4-nitropyridine andcyclohexen-1-ylboronic acid in step A to give 3-isobutylaniline. Thiswas followed by Method 1, steps C-H in Example 1, and using3-isobutylaniline in place of 2-methyl-4-phenoxyaniline in step C, andusing tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₄H₂₇N₅O₂S, 449.6; m/z found, 450.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.43 (s, 1H), 8.33-8.27 (m, 1H), 7.54-7.47 (m, 1H), 7.36-7.32(m, 1H), 7.25-7.19 (m, 2H), 6.12-6.05 (m, 1H), 4.32-4.17 (m, 1H),3.55-3.44 (m, 1H), 3.36-3.31 (m, 1H), 3.02-2.85 (m, 2H), 2.60-2.53 (m,2H), 2.15-1.99 (m, 2H), 1.96-1.69 (m, 3H), 0.95-0.91 (m, 6H).

Example 722:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, StepG, in Example 1, and using5-(*R)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 83) and 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one(Intermediate 15) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate. MS (ESI): mass calcd.for C₂₇H₃₀N₆O₃S, 518.6; m/z found, 519.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.43-8.39 (s, 1H), 8.38-8.30 (d, J=5.5 Hz, 1H), 7.44-7.37 (s,1H), 6.86-6.74 (m, 1H), 6.25-6.15 (d, J=16.5 Hz, 1H), 6.07-6.00 (d,J=5.5 Hz, 1H), 5.79-5.68 (m, 1H), 4.60-4.26 (m, 1H), 4.24-3.92 (m, 2H),3.25-3.11 (m, 1H), 3.00-2.84 (m, 1H), 2.76-2.69 (d, J=7.2 Hz, 2H),2.20-2.02 (m, 2H), 1.93-1.83 (m, 1H), 1.81-1.68 (m, 1H), 1.67-1.51 (m,1H), 1.05-0.90 (dd, J=6.8, 1.5 Hz, 6H).

Example 723:(R)-4-Oxo-5-(6-phenylpyrimidin-4-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 6-chloropyrimidin-4-amine andphenylboronic acid in place of 2-chloro-4-nitropyridine andcyclohexen-1-ylboronic acid and no Pd/C step in step A, and using Method1, steps C-H in Example 1, and using 6-phenylpyrimidin-4-amine in placeof 2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₄H₂₁N₇O₂S, 471.5; m/z found, 472.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ9.35-9.28 (m, 1H), 8.42 (s, 1H), 8.37-8.32 (m, 1H), 8.25-8.17 (m, 3H),7.58-7.50 (m, 3H), 6.61-6.55 (m, 1H), 4.30-4.20 (m, 1H), 3.54-3.44 (m,1H), 3.36-3.31 (m, 1H), 3.01-2.89 (m, 2H), 2.15-1.99 (m, 2H), 1.88-1.71(m, 2H).

Example 724:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(4-methyl-2-phenoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A, C-G, (including Chiral Separation Method A after stepF to obtain the *R atropisomer), in Example 1, and using2-chloro-4-methylpyrimidin-5-amine, 2-(dimethylamino)acetic acid, andCs₂CO₃ in place of 5-fluoro-2-nitrotoluene and K₂CO₃ in step A, and nostep B, and using 1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one(Intermediate 5), 1-propanephosphonic anhydride, anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G, to give the title compound. MS (ESI): masscalcd. for C₂₇H₂₃N₇O₄S, 541.6; m/z found, 542.0 [M+H]⁺. 1H NMR (400 MHz,MeOD) δ 8.55 (d, J=2.2 Hz, 1H), 8.38 (d, J=5.6 Hz, 1H), 7.49-7.42 (m,2H), 7.31-7.22 (m, 3H), 6.68-6.55 (m, 1H), 6.32-6.25 (m, 2H), 5.79-5.71(m, 1H), 4.70-4.55 (m, 1H), 4.05-3.46 (m, 4H), 2.40-2.03 (m, 5H).

Example 725:(R)-5-(4-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 4-bromo-1-methyl-2-nitrobenzene andphenylboronic acid in place of 2-chloro-4-nitropyridine andcyclohexen-1-ylboronic acid in step A, and using Method 1, steps C-H inExample 1, and using 2-methyl-5-phenylaniline in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₇H₂₅N₅O₂S, 483.6; m/z found, 484.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.28-8.16 (m, 1H), 7.75-7.67 (m, 1H), 7.65-7.60 (m, 2H), 7.58-7.56 (m,1H), 7.54-7.49 (m, 1H), 7.45-7.36 (m, 2H), 7.34-7.26 (m, 1H), 6.01-5.92(m, 1H), 4.26-4.12 (m, 1H), 3.40-3.31 (m, 1H), 3.20-3.10 (m, 1H),2.96-2.72 (m, 2H), 2.18 (s, 3H), 2.10-1.88 (m, 2H), 1.82-1.66 (m, 2H).

Example 12:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-cyclobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 672) was resolved by chiral SFC (Stationary phase: ChiralpakAS-H 5 μm 250*20 mm, Mobile phase: 70% CO₂, 30% MeOH) to yield the titlecompound. MS (ESI): mass calcd. for C₂₇H₂₈N₆O₄S, 532.6; m/z found, 533.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d, J=5.6 Hz, 1H), 8.06 (s, 1H),6.87-6.73 (m, 2H), 6.20 (d, J=16.7 Hz, 1H), 6.11 (d, J=5.6 Hz, 1H),5.79-5.69 (m, 1H), 5.24-5.12 (m, 1H), 4.58-4.26 (m, 1H), 4.21-3.91 (m,2H), 3.26-3.12 (m, 1H), 3.01-2.84 (m, 1H), 2.54-2.44 (m, 2H), 2.23-2.12(m, 5H), 2.11-2.03 (m, 1H), 1.92-1.83 (m, 2H), 1.79-1.67 (m, 2H),1.66-1.52 (m, 1H).

Example 727:(R)-5-(2-Isopropylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 2-chloro-4-nitropyridine and2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in place of2-chloro-4-nitropyridine and cyclohexen-1-ylboronic acid in step A, andusing Method 1, steps C-H in Example 1, and using2-isopropylpyridin-4-amine in place of 2-methyl-4-phenoxyaniline in stepC, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₂H₂₄N₆O₂S, 436.5; m/z found, 437.3 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.70 (d, J=5.3 Hz, 1H), 8.44 (s, 1H), 8.32 (d, J=5.6 Hz, 1H),7.49 (s, 1H), 7.39 (d, J=5.3 Hz, 1H), 6.20 (d, J=5.6 Hz, 1H), 4.32-4.21(m, 1H), 3.57-3.46 (m, 1H), 3.39-3.31 (m, 1H), 3.21-3.12 (m, 1H),3.01-2.90 (m, 2H), 2.14-2.01 (m, 2H), 1.92-1.70 (m, 2H), 1.34 (d, J=7.0Hz, 6H).

Example 728:(R)-5-(*R)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H, (including Chiral Resolution Method A after step Fto obtain the *R atropisomer) in Example 1, and using6-chloro-2-methyl-3-nitropyridine in place of 5-fluoro-2-nitrotoluene instep A, and using Pd/C in place of Fe in step B, and using tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate and diisopropylethylamine in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate andtriethylamine in step G, to give the title compound. MS (ESI): masscalcd. for C₂₅H₂₂N₆O₃S, 486.6; m/z found, 487.0 [M+H]⁺. ¹H NMR (600 MHz,CD₃OD): δ 8.60-8.56 (d, J=6.5 Hz, 1H), 7.93-7.87 (d, J=8.7 Hz, 1H),7.50-7.44 (m, 2H), 7.31-7.26 (m, 1H), 7.26-7.20 (m, 2H), 7.01-6.97 (d,J=8.6 Hz, 1H), 6.58-6.54 (d, J=6.5 Hz, 1H), 4.67-4.60 (m, 1H), 3.63-3.58(m, 2H), 3.48-3.36 (m, 2H), 2.49-2.39 (m, 1H), 2.32-2.30 (s, 3H),2.29-2.20 (m, 1H).

Example 729:(R)-5-(5-Methyl-2-phenylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 2-chloro-5-methylpyridin-4-amine, aceticanhydride, DMAP, and phenylboronic acid in place of2-chloro-4-nitropyridine and cyclohexen-1-ylboronic acid and no Pd/Creduction in step A, and using Method 1, steps C-H in Example 1, andusing 5-methyl-2-phenylpyridin-4-amine in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₆H₂₄N₆O₂S, 484.6; m/z found, 485.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.76 (s, 1H), 8.44 (s, 1H), 8.37-8.32 (m, 1H), 8.02-7.98 (m, 2H), 7.94(s, 1H), 7.53-7.41 (m, 3H), 6.20-6.12 (m, 1H), 4.32-4.22 (m, 1H),3.55-3.48 (m, 1H), 3.37-3.31 (m, 1H), 3.00-2.92 (m, 2H), 2.24 (s, 3H),2.12-2.03 (m, 2H), 1.88-1.71 (m, 2H).

Example 730:(R)-5-(4-(2-Isopropoxyethoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H, in Example 1, and using4-fluoro-2-methyl-1-nitrobenzene and 2-isopropoxyethanol in place of5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C in place ofFe in step B, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylatein place of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₆H₃₁N₅O₄S, 509.6; m/z found, 510.2 [M+H]+. ¹H NMR (400 MHz,CD₃OD): δ 8.01 (d, J=5.7 Hz, 1H), 7.12-7.07 (m, 1H), 7.02-6.97 (m, 1H),6.95-6.88 (m, 1H), 5.72 (d, J=5.7 Hz, 1H), 4.18-4.11 (m, 2H), 4.02-3.92(m, 1H), 3.83-3.78 (m, 2H), 3.76-3.69 (m, 1H), 3.21-3.12 (m, 1H),2.93-2.83 (m, 1H), 2.68-2.55 (m, 2H), 2.11 (s, 3H), 2.07-2.00 (m, 1H),1.85-1.75 (m, 1H), 1.69-1.52 (m, 2H), 1.19 (d, J=6.1, 6H).

Example 731:(R)-5-(2-Cyclohexylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps C-H in Example 1, and using 2-cyclohexylpyridin-4-amine(Example 677, step A) in place of 2-methyl-4-phenoxyaniline in step C,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₅H₂₈N₆O₂S, 476.6; m/z found, 477.2 [M+H]⁺. ¹H NMR (400 MHz,CD3OD and DMSO-d₆): δ 8.62 (d, J=5.3 Hz, 1H), 8.27-8.24 (m, 2H), 7.36(s, 1H), 7.27 (d, J=5.3 Hz, 1H), 6.10 (d, J=5.6 Hz, 1H), 4.24-4.16 (m,1H), 3.42-3.34 (m, 1H), 3.25-3.19 (m, 1H), 2.89-2.81 (m, 2H), 2.77-2.67(m, 1H), 1.97-1.63 (m, 9H), 1.56-1.45 (m, 2H), 1.41-1.30 (m, 2H),1.25-1.16 (m, 1H).

Example 732:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-isopropoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G, in Example 1, and using6-fluoro-2-methyl-3-nitropyridine and 2-propanol in place of5-fluoro-2-nitrotoluene and phenol in step A, and using Zn in place ofFe in step B, and using 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one(Intermediate 15), 1-propanephosphonic anhydride, anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G, to give the title compound. MS (ESI): masscalcd. for C₂₆H₂₈N₆O₄S, 520.6; m/z found, 521.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD): δ 8.35 (d, J=5.5 Hz, 1H), 7.60 (d, J=8.6 Hz, 1H), 6.85-6.70 (m,2H), 6.26-6.17 (m, 1H), 6.11 (d, J=5.5 Hz, 1H), 5.77-5.72 (m, 1H),5.39-5.29 (m, 1H), 4.58-4.26 (m, 1H), 4.20-3.92 (m, 2H), 3.22-3.12 (m,1H), 2.99-2.85 (m, 1H), 2.26 (s, 3H), 2.13-2.04 (m, 1H), 1.92-1.84 (m,1H), 1.81-1.68 (m, 1H), 1.65-1.54 (m, 1H), 1.40-1.34 (m, 6H).

Example 733:(R)-5-(3-Methyl-2-phenylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps C-H in Example 1, and using3-methyl-2-phenylpyridin-4-amine (Intermediate 48) in place of2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₆H₂₄N₆O₂S, 484.6; m/z found, 485.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.66 (d, J=5.2 Hz, 1H), 8.38 (d, J=5.5 Hz, 1H), 7.58-7.47 (m, 6H), 6.20(d, J=5.5 Hz, 1H), 4.31-4.23 (m, 1H), 3.55-3.47 (m, 1H), 3.37-3.32 (m,1H), 3.00-2.88 (m, 2H), 2.15 (s, 3H), 2.13-2.04 (m, 2H), 1.88-1.73 (m,2H).

Example 734:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-phenylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 2-chloro-6-methylpyridin-4-amine, aceticanhydride, and phenylboronic acid in place of 2-chloro-4-nitropyridineand cyclohexen-1-ylboronic acid and no Pd/C reduction in step A, andusing Method 1, steps C-I in Example 1, and using2-methyl-6-phenylpyridin-4-amine in place of 2-methyl-4-phenoxyanilinein step C, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₉H₂₆N₆O₃S, 538.6; m/z found, 539.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.31 (d, J=5.6 Hz, 1H), 8.04-7.98 (m, 2H), 7.82 (s, 1H),7.52-7.39 (m, 3H), 7.34 (s, 1H), 6.83-6.70 (m, 1H), 6.27 (d, J=5.5 Hz,1H), 6.22-6.11 (m, 1H), 5.77-5.62 (m, 1H), 4.57-4.26 (m, 1H), 4.22-3.90(m, 2H), 3.20-3.08 (m, 1H), 2.93-2.79 (m, 1H), 2.68 (s, 3H), 2.10-1.99(m, 1H), 1.89-1.79 (m, 1H), 1.78-1.62 (m, 1H), 1.59-1.45 (m, 1H).

Example 735:(R)-5-(2-Methyl-6-phenylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 2-chloro-6-methylpyridin-4-amine, aceticanhydride, and phenylboronic acid in place of 2-chloro-4-nitropyridineand cyclohexen-1-ylboronic acid and no Pd/C reduction in step A, andusing Method 1, steps C-H in Example 1, and using2-methyl-6-phenylpyridin-4-amine in place of 2-methyl-4-phenoxyanilinein step C, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₆H₂₄N₆O₂S, 484.6; m/z found, 485.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.47-8.42 (m, 1H), 8.40-8.27 (m, 1H), 8.07-7.97 (m, 2H), 7.79(s, 1H), 7.53-7.24 (m, 4H), 6.36-6.20 (m, 1H), 4.34-4.19 (m, 1H),3.62-3.49 (m, 1H), 3.27-3.13 (m, 1H), 3.01-2.87 (m, 2H), 2.74-2.60 (m,3H), 2.14-1.97 (m, 2H), 1.91-1.66 (m, 2H).

Example 13:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-cyclobutoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 672) was resolved by chiral SFC (Stationary phase: ChiralpakAS-H 5 m 250*20 mm, Mobile phase: 70% CO₂, 30% MeOH) to yield the titlecompound. MS (ESI): mass calcd. for C₂₇H₂₈N₆O₄S, 532.6; m/z found, 533.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.33 (d, J=5.5 Hz, 1H), 7.63 (d,J=8.6 Hz, 1H), 6.88-6.70 (m, 2H), 6.20 (dd, J=16.7, 4.7 Hz, 1H), 6.08(d, J=5.5 Hz, 1H), 5.73 (t, J=11.3 Hz, 1H), 5.26-5.16 (m, 1H), 4.61-4.25(m, 1H), 4.21-3.91 (m, 2H), 3.23-3.13 (m, 1H), 3.02-2.86 (m, 1H),2.55-2.44 (m, 2H), 2.25 (s, 3H), 2.21-2.11 (m, 2H), 2.08 (d, J=12.3 Hz,1H), 1.92-1.83 (m, 2H), 1.81-1.67 (m, 2H), 1.64-1.54 (m, 1H).

Example 737:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(3-methyl-2-phenylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps C-G, (including Chiral Resolution Method A after step Fto obtain the *S atropisomer) in Example 1, and using3-methyl-2-phenylpyridin-4-amine (Intermediate 48) in place of2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₉H₂₆N₆O₃S, 538.6; m/z found, 539.4 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.66 (d, J=4.9 Hz, 1H), 8.35 (d, J=5.3 Hz, 1H), 7.57-7.43 (m,6H), 6.83-6.71 (m, 1H), 6.24-6.12 (m, 2H), 5.78-5.66 (m, 1H), 4.60-4.28(m, 1H), 4.22-3.88 (m, 2H), 3.21-3.09 (m, 1H), 2.97-2.80 (m, 1H), 2.15(s, 3H), 2.09-2.00 (m, 1H), 1.90-1.82 (m, 1H), 1.79-1.66 (m, 1H),1.61-1.51 (m, 1H).

Example 738:(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(tetrahydro-2H-pyran-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-B, and using 3-tetrahydropyran-4-ylaniline (Intermediate47) in place of 3-cyclobutylaniline in step A, to yield the titlecompound. MS (ESI): mass calcd. for C₂₅H₂₇N₅O₃S, 477.6; m/z found, 478.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.49 (d, J=6.6 Hz, 1H), 7.60 (t,J=7.8 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.39 (s, 1H), 7.34-7.29 (m, 1H),6.38 (d, J=6.6 Hz, 1H), 4.35-4.26 (m, 1H), 4.08-4.00 (m, 2H), 3.61-3.52(m, 3H), 3.36 (d, J=12.8 Hz, 1H), 3.05-2.97 (m, 2H), 2.96-2.89 (m, 1H),2.15-2.06 (m, 2H), 1.92-1.75 (m, 6H).

Example 739: (R)-tert-Butyl3-(4-oxo-5-(3-(tetrahydro-2H-pyran-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared using the procedures found in Example534, step A, and using 3-tetrahydropyran-4-ylaniline (Intermediate 47)in place of 3-cyclobutylaniline in step A, to yield the title compound.MS (ESI): mass calcd. for C₃₀H₃₅N₅O₅S, 577.7; m/z found, 578.1 [M+H]⁺.¹H NMR (500 MHz, CD₃OD): δ 8.28 (d, J=5.6 Hz, 1H), 7.55 (t, J=7.8 Hz,1H), 7.46 (d, J=7.8 Hz, 1H), 7.35 (s, 1H), 7.28 (d, J=7.9 Hz, 1H), 6.08(d, J=5.6 Hz, 1H), 4.16-4.00 (m, 3H), 3.97-3.85 (m, 2H), 3.61-3.51 (m,2H), 3.01-2.73 (m, 3H), 2.06-1.98 (m, 1H), 1.86-1.74 (m, 5H), 1.68-1.50(m, 2H), 1.46 (s, 9H).

Example 740:(R)-4-Oxo-5-(6-phenylpyridazin-4-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using 6-chloropyridazin-4-amine andphenylboronic acid in place of 2-chloro-4-nitropyridine andcyclohexen-1-ylboronic acid and no Pd/C reduction in step A, and usingMethod 1, steps C-H in Example 1, and using 6-phenylpyridazin-4-amine inplace of 2-methyl-4-phenoxyaniline in step C, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₄H₂₁N₇O₂S, 471.5; m/z found, 472.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ9.38-9.26 (m, 1H), 8.50-8.39 (m, 2H), 8.33 (d, J=5.6 Hz, 1H), 8.19-8.10(m, 2H), 7.62-7.51 (m, 3H), 6.40 (d, J=5.6 Hz, 1H), 4.30-4.20 (m, 1H),3.55-3.47 (m, 1H), 3.36-3.30 (m, 1H), 3.02-2.92 (m, 2H), 2.11-2.00 (m,2H), 1.89-1.69 (m, 2H).

Example 741:(R)-4-Oxo-5-(6-phenoxypyridin-3-yl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H, in Example 1, and using 2-chloro-5-nitropyridine inplace of 5-fluoro-2-nitrotoluene in step A, and using Pd/C in place ofFe in step B, and using tert-butyl (3R)-3-aminopyrrolidine-1-carboxylatein place of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₄H₂₀N₆O₃S, 472.5; m/z found, 473.0 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): δ 9.46 (s, 1H), 8.15 (s, 2H), 7.76 (s, 2H), 7.26 (s, 6H), 5.98(s, 1H), 4.74 (d, J=71.0 Hz, 1H), 3.49 (s, 5H), 2.18 (t, J=61.7 Hz, 2H).

Example 742:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsD-I in Example 1, and using2-chloro-4-(2-methyl-4-tetrahydropyran-4-yloxyanilino)pyridine-3-carbonitrile(Intermediate 31) in place of2-chloro-4-(2-methyl-4-phenoxyanilino)pyridine-3-carbonitrile in step D,and using Chiral Resolution Method A after step F to obtain the *Satropisomer, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylatein place of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₉H₃₁N₅O₅S,561.7; m/z found, 562.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.31-8.27 (m,1H), 7.25-7.20 (m, 1H), 7.05-7.01 (m, 1H), 6.99-6.95 (m, 1H), 6.81-6.77(m, 1H), 6.22-6.17 (m, 1H), 6.04-6.00 (m, 1H), 5.74-5.69 (m, 1H),4.68-4.58 (m, 1H), 4.33-4.11 (m, 1H), 4.07-3.85 (m, 4H), 3.65-3.57 (m,2H), 3.21-3.18 (m, 1H), 2.93-2.86 (m, 1H), 2.11 (s, 3H), 2.09-2.02 (m,3H), 1.89-1.83 (m, 1H), 1.80-1.69 (m, 3H), 1.55-1.50 (m, 1H)

Example 743: (R)-tert-Butyl3-(5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared using the procedures found in Example534, step A, and using 2-methyl-6-phenoxypyridin-3-amine (Intermediate49) in place of 3-cyclobutylaniline in step A, to yield the titlecompound. MS (ESI): mass calcd. for C₃₁H₃₂N₆O₅S, 600.7; m/z found, 601.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.36 (d, J=5.5 Hz, 1H), 7.79 (d,J=8.6 Hz, 1H), 7.47-7.42 (m, 2H), 7.28-7.23 (m, 1H), 7.21-7.18 (m, 2H),6.91 (d, J=8.6 Hz, 1H), 6.15 (dd, J=5.5, 1.7 Hz, 1H), 4.08-4.01 (m, 1H),3.97-3.83 (m, 2H), 3.07-2.76 (m, 2H), 2.25 (s, 3H), 2.05-2.01 (m, 1H),1.82-1.76 (m, 1H), 1.67-1.51 (m, 2H), 1.46 (s, 9H).

Example 744:(R)-5-(6-Cyclobutoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using the procedures found in Example534, steps A-B, and using 6-(cyclobutoxy)pyridin-3-amine in place of3-cyclobutylaniline in step A, to yield the title compound. MS (ESI):mass calcd. for C₂₃H₂₄N₆O₃S, 464.5; m/z found, 465.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD): δ 8.57 (d, J=6.7 Hz, 1H), 8.32 (d, J=2.5 Hz, 1H), 7.93 (dd,J=8.9, 2.7 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 6.63 (d, J=6.7 Hz, 1H),5.31-5.20 (m, 1H), 4.35-4.25 (m, 1H), 3.54 (dd, J=12.3, 4.1 Hz, 1H),3.36 (d, J=13.7 Hz, 1H), 3.01 (t, J=11.5 Hz, 2H), 2.60-2.48 (m, 2H),2.28-2.17 (m, 2H), 2.15-2.06 (m, 2H), 1.95-1.70 (m, 4H).

Example 14:N-((3*S,4*R)-4-Acrylamidotetrahydrofuran-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A purification was performed on Example 668 using chiral SFC (Stationaryphase: CHIRALPAK IC 5 m 250×21 mm, Mobile phase: 45% CO₂, 55% EtOH) togive the title compound as the single enantiomer. MS (ESI): mass calcd.for C₂₈H₂₄N₆O₅S, 556.6; m/z found, 557.0 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.40-8.31 (d, J=5.5 Hz, 1H), 8.13-8.02 (s, 1H), 7.50-7.40 (m,2H), 7.30-7.15 (m, 3H), 7.10-7.01 (s, 1H), 6.35-6.13 (m, 3H), 5.70-5.59(dd, J=9.7, 2.3 Hz, 1H), 4.81-4.67 (m, 2H), 4.17-4.03 (m, 2H), 3.88-3.75(m, 2H), 2.24-2.14 (s, 3H).

Example 746:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-methyl-2-phenoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A, C-I, (including Chiral Resolution Method A after stepF to obtain the *S atropisomer), in Example 1, and using2-chloro-4-methylpyrimidin-5-amine, 2-(dimethylamino)acetic acid, andCs₂CO₃ in place of 5-fluoro-2-nitrotoluene and K₂CO₃ in step A, and nostep B, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G, and using prop-2-enoyl prop-2-enoate anddiisopropylethylamine in place of prop-2-enoyl chloride andtriethylamine in step I, to give the title compound. MS (ESI): masscalcd. for C₂₈H₂₅N₇O₄S, 555.6; m/z found, 556.0 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ 8.38 (d, J=6.2 Hz, 2H), 7.50-7.40 (m, 2H), 7.33-7.21 (m, 3H),6.69-6.53 (m, 1H), 6.33 (dd, J=32.8, 16.8 Hz, 1H), 6.08-6.02 (m, 1H),5.72 (s, 1H), 5.30 (s, 2H), 4.17-4.02 (m, 2H), 3.56 (s, 1H), 3.29 (s,1H), 2.38 (d, J=6.1 Hz, 3H), 2.04 (s, 3H), 1.71-1.60 (m, 1H), 1.26 (t,J=7.1 Hz, 1H).

Example747:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Example 1,Method 1, Steps G-I, using5-(*S)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 82) and tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in step G. MS (ESI): mass calcd.for C₂₆H₂₈N₆O₃S, 504.6; m/z found, 505.0 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): δ 10.74 (s, 1H), 8.40 (d, J=3.1 Hz, 1H), 8.03 (s, 1H), 7.21 (s,1H), 6.50-6.32 (m, 1H), 6.00 (s, 1H), 5.97-5.91 (m, 1H), 5.70 (ddt,J=19.1, 9.9, 1.7 Hz, 1H), 4.70 (dq, J=17.5, 5.6 Hz, 1H), 3.86-3.58 (m,4H), 3.12 (q, J=7.4 Hz, 1H), 2.71 (d, J=7.2 Hz, 2H), 2.38 (s, 3H),1.94-1.37 (m, 3H), 0.99 (d, J=6.6 Hz, 6H).

Example 748:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(2-phenoxypyrimidin-5-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G, in Example 1, and using 2-chloro-5-nitropyrimidinein place of 5-fluoro-2-nitrotoluene in step A, and Pd/C in place of Fein step B, and using 1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one(Intermediate 5) in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₆H₂₁N₇O₄S, 527.6; m/z found, 528.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 10.36 (s, 1H), 8.78 (s, 2H), 8.50-8.32 (m, 2H), 7.54-7.43 (m, 2H),7.35-7.24 (m, 3H), 6.68-6.50 (m, 1H), 6.45-6.36 (m, 1H), 6.19-6.06 (m,1H), 5.72-5.61 (m, 1H), 4.58-4.38 (m, 1H), 3.92-3.37 (m, 4H), 2.27-1.84(m, 2H).

Example 749:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-phenoxypyrimidin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A, C-G, in Example 1, and using5-bromopyrimidin-2-amine, N,N-dimehtylglycine, CuI, dioxane, and Cs₂CO₃in place of 5-fluoro-2-nitrotoluene, K₂CO₃, and DMF in step A, and nostep B, and using 1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one(Intermediate 5) in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to give the title compound. MS (ESI): mass calcd. forC₂₆H₂₁N₇O₄S, 527.6; m/z found, 528.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.68 (s, 2H), 8.32-8.24 (m, 1H), 7.53-7.44 (m, 2H), 7.36-7.21 (m, 3H),6.68-6.52 (m, 1H), 6.31-6.21 (m, 2H), 5.78-5.68 (m, 1H), 4.65-4.56 (m,1H), 4.02-3.52 (m, 4H), 2.40-2.00 (m, 2H).

Example 750:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isobutylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inExample 677, step A, and using isobutylboronic acid and1-bromo-4-nitrobenzene in place of cyclohexen-1-ylboronic acid and2-chloro-4-nitropyridine in step A, and using Method 1, steps C-G inExample 1, and using 4-isobutylaniline in place of2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₇H₂₉N₅O₃S, 503.6; m/z found, 504.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.38-8.28 (m, 1H), 7.44-7.37 (m, 2H), 7.35-7.29 (m, 2H),6.85-6.71 (m, 1H), 6.24-6.12 (m, 2H), 5.77-5.66 (m, 1H), 4.61-3.89 (m,3H), 3.24-3.09 (m, 1H), 2.98-2.80 (m, 1H), 2.64-2.54 (m, 2H), 2.12-2.00(m, 1H), 1.99-1.80 (m, 2H), 1.77-1.64 (m, 1H), 1.63-1.50 (m, 1H),0.98-0.92 (m, 6H)

Example 751:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenylpyridazin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 3-chloro-5-phenylpyridazine

A solution of 3,5-dichloropyridazine (2.00 g, 13.4 mmol), phenylboronicacid (1.64 g, 13.4 mmol), Pd(OAc)₂ (301 mg, 1.34 mmol),1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (1.91 g, 33.6mmol), KF (1.95 g, 33.6 mmol), dioxane (50 mL), and water (12 mL) wasstirred at reflux for 15 h under N2. The reaction was diluted withEtOAc, washed with brine, dried over anhydrous Na₂SO₄, and concentratedto dryness. The residue was purified by normal phase flash columnchromatography (SiO₂) to give the title compound (1.53 g, 59.8% yield)as a white solid. MS (ESI): mass calcd. for C₁₀H₇ClN₂, 190.63; m/zfound, 191.0 [M+H]⁺.

Step B: tert-Butyl (5-phenylpyridazin-3-yl)carbamate

The solution of 3-chloro-5-phenylpyridazine (1.53 g, 8.03 mmol),tert-butyl carbamate (1.88 g, 16.1 mmol), Pd(dppf)Cl₂ (0.592 g, 0.803mmol)), Xphos (0.928 g, 1.61 mmol), and Cs₂CO₃ (6.538 g, 20.06 mmol) indioxane (30 mL) was stirred at 100° C. for 16 hours. The reaction wasdiluted with EtOAc and filtered. The filtrate was partitioned betweenEtOAc and water, the organic layer collected and washed with water andbrine, dried over anhydrous Na₂SO₄, and concentrated to dryness. Theresidue was purified by normal phase flash column chromatography (SiO₂)to give the title compound (0.96 g, 44% yield) as light yellow solid. MS(ESI): mass calcd. for C₁₅H₁₇N₃O₂, 271.31; m/z found, 272.0 [M+H]⁺.

Step C: 5-phenylpyridazin-3-amine

A solution of tert-butyl (5-phenylpyridazin-3-yl)carbamate 0.96 g, 3.5mmol), TFA (5 mL), and DCM (20 mL) was stirred at room temperature for 1h. The mixture was concentrated to dryness to give the title compound(0.52 g, 86% yield) as light yellow liquid. MS (ESI): mass calcd. forC₁₀H₉N₃, 171.20; m/z found, 172.1 [M+H]⁺.

Step D:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenylpyridazin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps C-G in Example 1, and using 5-phenylpyridazin-3-amine inplace of 2-methyl-4-phenoxyaniline in step C, and using(R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₃N₇O₃S,525.6; m/z found, 526.6 [M+H]⁺. ¹H NMR (400 MHz, a mixture of CD3OD andDMSO-d₆): δ 9.75-9.70 (m, 1H), 8.35-8.30 (m, 1H), 8.29-8.24 (m, 1H),7.93-7.87 (m, 2H), 7.58-7.49 (m, 3H), 6.78-6.68 (m, 1H), 6.33-6.28 (m,1H), 6.15-6.06 (m, 1H), 5.68-5.61 (m, 1H), 4.52-4.15 (m, 1H), 4.12-3.89(m, 1H), 3.89-3.79 (m, 1H), 3.12-2.96 (m, 1H), 2.85-2.64 (m, 1H),2.01-1.91 (m, 1H), 1.82-1.73 (m, 1H), 1.73-1.59 (m, 1H), 1.53-1.35 (m,1H).

Example 15:N-((*3R,*4S)-4-Acrylamidotetrahydrofuran-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A purification was performed on Example 668 using chiral SFC (Stationaryphase: CHIRALPAK IC 5 μm 250×21 mm, Mobile phase: 45% CO₂, 55% EtOH) togive the title compound as the single enantiomer. MS (ESI): mass calcd.for C₂₈H₂₄N₆O₅S, 556.6; m/z found, 557.0 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.40-8.30 (d, J=5.6 Hz, 1H), 8.14-8.06 (s, 1H), 7.51-7.40 (m,2H), 7.31-7.14 (m, 3H), 7.09-7.01 (s, 1H), 6.34-6.12 (m, 3H), 5.70-5.60(dd, J=9.5, 2.3 Hz, 1H), 4.82-4.67 (m, 2H), 4.17-4.04 (m, 2H), 3.88-3.75(m, 2H), 2.24-2.16 (s, 3H).

Example 753:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isopropoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G, (including Chiral Resolution Method A after step Fto obtain the *S atropisomer) in Example 1, and using6-fluoro-2-methyl-3-nitropyridine, 2-propanol, acetonitrile, and Cs₂CO₃in place of 5-fluoro-2-nitrotoluene, phenol, DMF, and K₂CO₃ in step A,and using Zn in place of Fe in step B, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15),1-propanephosphonic anhydride, and diisopropylethylamine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G, to give the title compound. MS (ESI): masscalcd. for C₂₆H₂₈N₆O₄S, 520.6; m/z found, 521.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD): δ 8.34 (d, J=5.5 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 6.84-6.75 (m,1H), 6.73 (d, J=8.6 Hz, 1H), 6.20 (d, J=17.0 Hz, 1H), 6.10 (d, J=5.5 Hz,1H), 5.78-5.71 (m, 1H), 5.40-5.31 (m, 1H), 4.58-4.48 (m, 0.5H), 4.24(dd, J=63.6, 12.6 Hz, 1H), 4.05-3.91 (m, 1.5H), 3.23-3.15 (m, 1H),3.00-2.87 (m, 1H), 2.26 (s, 3H), 2.07 (d, J=10.6 Hz, 1H), 1.92-1.84 (m,1H), 1.82-1.68 (m, 1H), 1.66-1.54 (m, 1H), 1.37 (dd, J=6.1, 2.8 Hz, 6H).

Example 754:(R)-5-(4-Isobutylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described instep A of Example 677, and using isobutylboronic acid and1-bromo-4-nitrobenzene in place of cyclohexen-1-ylboronic acid and2-chloro-4-nitropyridine, and using Method 1, steps C-H in Example 1,using 4-isobutylaniline in place of 2-methyl-4-phenoxyaniline in step C,and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, to give the title compound. MS (ESI): masscalcd. for C₂₄H₂₇N₅O₂S, 449.6; m/z found, 450.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.41 (s, 1H), 8.32-8.25 (m, 1H), 7.44-7.36 (m, 2H), 7.34-7.26(m, 2H), 6.13-6.05 (m, 1H), 4.32-4.20 (m, 1H), 3.57-3.46 (m, 1H),3.38-3.32 (m, 1H), 3.01-2.85 (m, 2H), 2.62-2.54 (m, 2H), 2.14-2.00 (m,2H), 1.99-1.90 (m, 1H), 1.86-1.68 (m, 2H), 0.98-0.93 (m, 6H).

Example 755:(R)-4-Oxo-5-(5-phenylpyridazin-3-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: tert-Butyl (5-phenylpyridazin-3-yl)carbamate

A mixture of 3-chloro-5-phenylpyridazine (1.53 g, 8.03 mmol), tert-butylcarbamate (1.88 g, 16.05 mmol),[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.59 g,0.80 mmol), 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.93g, 1.6 mmol), and cesium carbonate (6.54 g, 20 mmol) in dioxane (30 mL)was stirred at 100° C. for 16 hr. The mixture was diluted with EtOAc andfiltered. The filtrate was partitioned between EtOAc and water. Theorganic layer was washed with water and brine, then dried over Na₂SO₄and concentrated to give the crude product, which was purified by ISCO(pentane/EtOAc) to get pure product (0.96 g, 44% yield) as light yellowsolid.

Step B: tert-Butyl(2-chloro-3-cyanopyridin-4-yl)(5-phenylpyridazin-3-yl)carbamate

A solution of tert-butyl (5-phenylpyridazin-3-yl)carbamate (0.96 g, 3.5mmol), 2-chloro-4-iodopyridine-3-carbonitrile (1.216 g, 4.600 mmol),Pd(OAc)₂ (79 mg, 0.35 mmol), DPEphos (381 mg, 0.708 mmol), Cs₂CO₃ (2.30g, 7.08 mmol), in dioxane (20 mL) in a flask was stirred at 100° C. for2 h under N₂. The reaction was concentrated to dryness and purified bynormal phase flash column chromatography (SiO₂) to give the titlecompound (1.02 g, 70.7% yield) as a light yellow solid. MS (ESI): masscalcd. for C₂₁H₁₈ClN₅O₂, 407.85; m/z found, 352.2 (minus t-butyl group)[M+H]⁺.

Step C: Methyl3-amino-4-((tert-butoxycarbonyl)(5-phenylpyridazin-3-yl)amino)thieno[2,3-b]pyridine-2-carboxylate

A solution of tert-butyl(2-chloro-3-cyanopyridin-4-yl)(5-phenylpyridazin-3-yl)carbamate (1.02 g,2.50 mmol), methyl 2-mercaptoacetate (0.398 g, 3.75 mmol), and Cs₂CO₃(1.219 g, 3.715 mmol) in dioxane (20 mL) in a flask was stirred at 100°C. for 2 h. The reaction was concentrated to dryness and purified bynormal phase flash column chromatography (SiO₂) to give the titlecompound (1.05 g, 87.9% yield) as light yellow solid. MS (ESI): masscalcd. for C₂₁H₁₈ClN₅O₂, 477.54; m/z found, 478.3 [M+H]⁺.

Step D: Methyl3-amino-4-((5-phenylpyridazin-3-yl)amino)thieno[2,3-b]pyridine-2-carboxylate

A solution of methyl3-amino-4-((tert-butoxycarbonyl)(5-phenylpyridazin-3-yl)amino)thieno[2,3-b]pyridine-2-carboxylate(1.05 g, 2.20 mmol) in TFA (4 mL) and DCM (12 mL) was stirred at roomtemperature for 3 h. The reaction was concentrated to dryness to givethe title compound (0.79 g, 95% yield) as a yellow solid, which was usedin the next step directly. MS (ESI): mass calcd. for C₁₉H₁₅N₅O₂S,377.42; m/z found, 378.3 [M+H]⁺.

Step E:(R)-4-Oxo-5-(5-phenylpyridazin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps E-H, in Example 1, and using methyl3-amino-4-((5-phenylpyridazin-3-yl)amino)thieno[2,3-b]pyridine-2-carboxylatein place of methyl3-amino-4-(2-methyl-4-phenoxyanilino)thieno[2,3-b]pyridine-2-carboxylatein step E, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate inplace of 5-fluoro-2-nitrotoluene in step G, to give the title compound.MS (ESI): mass calcd. for C₂₄H₂₁N₇O₂S, 471.5; m/z found, 472.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): δ 9.74-9.70 (m, 1H), 8.87-8.80 (m, 1H),8.18-8.12 (m, 3H), 7.99-7.93 (m, 2H), 7.61-7.52 (m, 3H), 6.14-6.10 (m,1H), 4.13-4.07 (m, 1H), 4.00-3.40 (br, 1H), 3.37-3.30 (m, 1H), 3.17-3.09(m, 1H), 2.89-2.76 (m, 2H), 1.99-1.81 (m, 2H), 1.72-1.54 (m, 2H).

Example 756:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps G-I, in Example 1 and using5-(*R)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 83) and tert-butyl(3R)-3-aminopyrrolidine-1-carboxylate in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₆H₂₈N₆O₃S, 504.6; m/z found, 505.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.44 (d, J=2.5 Hz, 1H), 8.33 (dd,J=5.5, 1.4 Hz, 1H), 7.41 (s, 1H), 6.68-6.54 (m, 1H), 6.32-6.24 (m, 1H),6.03 (dd, J=5.5, 1.7 Hz, 1H), 5.79-5.71 (m, 1H), 4.70-4.57 (m, 1H), 4.01(dd, J=10.8, 6.8 Hz, 0.5H), 3.90-3.79 (m, 1H), 3.77-3.67 (m, 1H),3.63-3.56 (m, 1H), 3.55-3.49 (m, 0.5H), 2.73 (d, J=7.3 Hz, 2H),2.39-2.25 (m, 1H), 2.23 (s, 3H), 2.19-2.05 (m, 2H), 0.99 (dd, J=6.6, 1.7Hz, 6H).

Example 757:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isopropoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G, (including chiral resolution Method A after step Fto obtain the *R atropisomer), in Example 1, and using6-fluoro-2-methyl-3-nitropyridine, 2-propanol, acetonitrile, and Cs₂CO₃in place of 5-fluoro-2-nitrotoluene, phenol, DMF, and K₂CO₃ in step A,and using Zn in place of Fe in step B, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15),1-propanephosphonic anhydride, and diisopropylethylamine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G. MS (ESI): mass calcd. for C₂₆H₂₈N₆O₄S, 520.6;m/z found, 521.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): δ 8.34 (d, J=5.5 Hz,1H), 7.59 (d, J=8.6 Hz, 1H), 6.85-6.75 (m, 1H), 6.74 (d, J=8.6 Hz, 1H),6.24-6.17 (m, 1H), 6.10 (d, J=5.6 Hz, 1H), 5.74 (t, J=9.9 Hz, 1H),5.40-5.31 (m, 1H), 4.59-4.49 (m, 0.5H), 4.24 (dd, J=61.0, 13.1 Hz, 1H),4.04-3.93 (m, 1.5H), 3.24-3.14 (m, 1H), 2.99-2.83 (m, 1H), 2.26 (s, 3H),2.12-2.04 (m, 1H), 1.92-1.84 (m, 1H), 1.82-1.68 (m, 1H), 1.66-1.54 (m,1H), 1.37 (dd, J=6.1, 2.9 Hz, 6H).

Example 758:(R)-5-(*S)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A, C-H, (including Chiral Resolution Method A after stepF to obtain the *S atropisomer) in Example 1, and using6-bromo-4-methylpyridin-3-amine,1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloridedichloromethane complex, THF, and bromo(isobutyl)zinc in place of5-fluoro-2-nitrotoluene, DMF, phenol, and K₂CO₃ in step A, and no stepB, and using tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₃H₂₆N₆O₂S,450.6; m/z found, 451.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 8.73-8.10 (m,1H), 7.83 (d, J=7.1 Hz, 1H), 7.23 (d, J=36.1 Hz, 2H), 5.94 (s, 1H),3.69-3.50 (m, 1H), 3.10-2.70 (m, 6H), 2.71 (d, J=7.2 Hz, 1H), 2.28 (s,3H), 2.00 (s, 1H), 1.94-1.69 (m, 3H), 0.99 (d, J=6.6 Hz, 6H).

Example 759:(R)-5-(*S)-(6-Isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H, (including Chiral Resolution Method A after step Fto obtain the *S atropisomer), in Example 1, and using2-fluoro-4-methyl-5-nitropyridine, 2-methyl-1-propanol, acetonitrile,and Cs₂CO₃ in place of 5-fluoro-2-nitrotoluene, phenol, DMF, and K₂CO₃in step A, and using Pd/C in place of Fe in step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate, 1-propanephosphonic anhydride, anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G. MS (ESI): mass calcd. for C₂₄H₂₈N₆O₃S, 480.6;m/z found, 481.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.36-8.26 (m, 1H),8.04 (d, J=17.0 Hz, 1H), 6.79 (s, 1H), 6.24 (s, 1H), 6.01 (d, J=5.5 Hz,1H), 4.21 (s, 1H), 4.15-4.02 (m, 2H), 3.47 (s, 2H), 3.19 (dd, J=12.2,3.5 Hz, 1H), 3.05-2.80 (m, 3H), 2.20-2.03 (m, 4H), 1.93-1.73 (m, 2H),1.39-1.29 (m, 2H), 1.03 (dd, J=6.8, 1.2 Hz, 6H).

Example 760:(R)-5-(*R)-(6-Isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H, (including chiral resolution Method A after step Fto obtain the *R atropisomer), in Example 1, and using2-fluoro-4-methyl-5-nitropyridine, 2-methyl-1-propanol, acetonitrile,and Cs₂CO₃ in place of 5-fluoro-2-nitrotoluene, phenol, DMF, and K₂CO₃in step A, and using Pd/C in place of Fe in step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate, 1-propanephosphonic anhydride, anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G. MS (ESI): mass calcd. for C₂₄H₂₈N₆O₃S, 480.6;m/z found, 481.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 8.36 (d, J=5.5 Hz,1H), 8.01 (s, 1H), 6.81-6.75 (m, 1H), 6.24 (s, 1H), 6.04 (d, J=5.5 Hz,1H), 4.18-4.04 (m, 3H), 3.47 (s, 2H), 3.19 (dd, J=12.2, 3.5 Hz, 1H),3.07 (dd, J=11.7, 3.0 Hz, 1H), 2.89-2.76 (m, 3H), 2.17-2.05 (m, 3H),1.77 (dtd, J=27.2, 9.1, 8.3, 3.8 Hz, 2H), 1.39-1.29 (m, 2H), 1.03 (dd,J=6.7, 1.4 Hz, 6H).

Example 761:(R)-5-(*S)-(6-(Cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H, (including Chiral Resolution Method A after step Fto obtain the *S atropisomer), in Example 1, and using2-fluoro-4-methyl-5-nitropyridine, cyclopentanol, and Cs₂CO₃ in place of5-fluoro-2-nitrotoluene, phenol, and K₂CO₃ in step A, and using Pd/C inplace of Fe in step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate, 1-propanephosphonic anhydride, anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G, to give the title compound. MS (ESI): masscalcd. for C₂₅H₂₈N₆O₃S, 492.6; m/z found, 493.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ 8.36 (d, J=5.4 Hz, 1H), 8.00 (s, 1H), 6.75-6.68 (m, 1H), 6.25(s, 1H), 6.04 (d, J=5.5 Hz, 1H), 5.42 (tt, J=6.2, 2.9 Hz, 1H), 4.13(ddq, J=9.3, 6.1, 3.1 Hz, 1H), 3.49 (s, 2H), 3.08 (dd, J=11.7, 3.1 Hz,1H), 2.90-2.72 (m, 3H), 2.13 (d, J=0.8 Hz, 3H), 2.05-1.90 (m, 2H),1.92-1.53 (m, 10H).

Example 762:(R)-5-(*R)-(6-(Cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H, (including chiral resolution Method A after step Fto obtain the *R atropisomer), in Example 1, and using2-fluoro-4-methyl-5-nitropyridine, cyclopentanol, and Cs₂CO₃ in place of5-fluoro-2-nitrotoluene, phenol, and K₂CO₃ in step A, and using Pd/C inplace of Fe in step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate, 1-propanephosphonic anhydride, anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G, to give the title compound. MS (ESI): masscalcd. for C₂₅H₂₈N₆O₃S, 492.6; m/z found, 493.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): δ 8.32 (d, J=5.4 Hz, 1H), 8.04 (s, 1H), 6.72 (s, 1H), 6.47-6.42(m, 1H), 6.02 (d, J=5.4 Hz, 1H), 5.42 (tt, J=6.3, 2.7 Hz, 1H), 4.43 (s,4H), 4.13 (tp, J=6.4, 3.1 Hz, 1H), 3.08 (dd, J=11.7, 3.2 Hz, 1H),2.90-2.77 (m, 1H), 2.12 (s, 3H), 1.98 (qdd, J=9.1, 7.3, 6.0, 3.7 Hz,2H), 1.90-1.70 (m, 7H), 1.69-1.51 (m, 3H).

Example 763:(R)-5-(*S)-(4-Methyl-2-phenoxypyrimidin-5-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A, C-H, (including Chiral Resolution Method A after stepF to obtain the *S atropisomer), in Example 1, and using2-chloro-4-methylpyrimidin-5-amine, CuI, N,N-dimethylglycine, and Cs₂CO₃in place of 5-fluoro-2-nitrotoluene, DMF, and K₂CO₃ in step A, and usingno step B, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and triethylamine instep G. MS (ESI): mass calcd. for C₂₅H₂₃N₇O₃S, 501.6; m/z found, 502.0[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.43-8.32 (m, 2H), 7.51-7.41(m, 2H), 7.34-7.21 (m, 2H), 6.43 (d, J=7.4 Hz, 1H), 6.04 (d, J=5.5 Hz,1H), 3.63 (s, 5H), 3.11 (dd, J=11.7, 3.1 Hz, 1H), 2.87 (dtd, J=21.8,11.7, 5.3 Hz, 3H), 2.38 (s, 3H), 1.80 (ddt, J=17.5, 14.0, 5.8 Hz, 3H).

Example 764:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-isobutyl-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A, C-H, in Example 1, and using6-bromo-2-methylpyridin-3-amine,1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloridedichloromethane complex, THF, and bromo(isobutyl)zinc in place of5-fluoro-2-nitrotoluene, DMF, phenol, and K₂CO₃ in step A, and no stepB, and using 1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate15), PYOXIM, and diisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G. MS (ESI): mass calcd. for C₂₇H₃₀N₆O₃S, 518.6;m/z found, 519.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34 (d, J=5.5 Hz,1H), 7.77 (dd, J=8.1, 1.2 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 6.87-6.74 (m,1H), 6.20 (d, J=16.5 Hz, 1H), 6.02 (dd, J=5.5, 1.8 Hz, 1H), 5.79-5.68(m, 1H), 4.43 (dd, J=92.3, 12.9 Hz, 1H), 4.22-3.91 (m, 2H), 3.21-3.12(m, 1H), 2.90 (q, J=11.7 Hz, 1H), 2.73 (d, J=7.3 Hz, 2H), 2.38 (s, 3H),2.18-2.03 (m, 2H), 1.94-1.84 (m, 1H), 1.82-1.68 (m, 1H), 1.64-1.53 (m,1H), 0.99 (dd, J=6.6, 1.9 Hz, 6H).

Example 765:(R)-5-(*S)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H, (including Chiral Resolution Method A after step Fto obtain the *S atropisomer), in Example 1, and using6-bromo-4-methylpyridin-3-amine,1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloridedichloromethane complex, THF, and bromo(isobutyl)zinc in place of5-fluoro-2-nitrotoluene, DMF, phenol, and K₂CO₃ in step A, and no stepB, and using tert-butyl (3R)-3-aminopiperidine-1-carboxylate,1-propanephosphonic anhydride, and diisopropylethylamine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G.

Step B:(R)-5-(*S)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using(R)-5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,propanoyl propanoate and diisopropylethylamine. MS (ESI): mass calcd.for C₂₇H₃₂N₆O₃S, 520.7; m/z found, 521.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): δ 9.55 (s, 1H), 8.44-8.31 (m, 2H), 7.20 (s, 1H), 5.96 (dd,J=11.0, 5.6 Hz, 1H), 3.69-3.32 (m, 5H), 2.98 (t, J=11.0 Hz, 2H),2.25-2.12 (m, 2H), 2.05 (s, 3H), 1.82-1.75 (m, 1H), 1.32-1.14 (m, 8H),0.99 (d, J=6.7 Hz, 6H).

Example 766:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H, (including Chiral Resolution Method A after step F to obtain the *Satropisomer), in Example 1, and using 2-fluoro-4-methyl-5-nitropyridine,2-methyl-1-propanol, acetonitrile, and Cs₂CO₃ in place of5-fluoro-2-nitrotoluene, phenol, DMF, and K₂CO₃ in step A, and usingPd/C in place of Fe in step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate, 1-propanephosphonic anhydride, anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using(R)-5-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamideprop-2-enoyl prop-2-enoate and diisopropylethylamine. MS (ESI): masscalcd. for C₂₇H₃₀N₆O₄S, 534.6; m/z found, 535.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): δ 9.58 (s, 1H), 8.32 (d, J=5.5 Hz, 1H), 8.05 (s, 1H), 6.80 (s,1H), 6.70-6.58 (m, 2H), 6.32 (dd, J=35.3, 16.8 Hz, 1H), 6.03 (d, J=5.6Hz, 1H), 5.78-5.67 (m, 1H), 4.09 (tdd, J=17.6, 11.5, 5.2 Hz, 5H), 2.69(s, 1H), 2.17-2.00 (m, 6H), 1.72-1.59 (m, 2H), 1.26 (t, J=7.1 Hz, 1H),1.03 (d, J=6.7 Hz, 6H).

Example 767:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared Method 1, steps A-H, (including chiralresolution Method A after step F to obtain the *R atropisomer), inExample 1, and using 2-fluoro-4-methyl-5-nitropyridine,2-methyl-1-propanol, acetonitrile, and Cs₂CO₃ in place of5-fluoro-2-nitrotoluene, phenol, DMF, and K₂CO₃ in step A, and usingPd/C in place of Fe in step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate, 1-propanephosphonic anhydride, anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using(R)-5-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,prop-2-enoyl prop-2-enoate and diisopropylethylamine. MS (ESI): masscalcd. for C₂₇H₃₀N₆O₄S, 534.6; m/z found, 535.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): δ 9.49 (s, 1H), 8.35 (d, J=5.5 Hz, 1H), 8.03 (s, 1H), 6.80 (s,1H), 6.64 (d, J=14.1 Hz, 1H), 6.04 (d, J=5.7 Hz, 2H), 5.74 (s, 1H),4.18-4.01 (m, 4H), 3.56 (s, 1H), 3.29 (s, 1H), 2.18-1.96 (m, 7H), 1.79(s, 1H), 1.26 (t, J=7.1 Hz, 2H), 1.03 (dd, J=6.7, 1.2 Hz, 6H).

Example 768:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H, (including Chiral Resolution Method A after step Fto obtain the *S atropisomer), in Example 1, and using2-fluoro-4-methyl-5-nitropyridine, cyclopentanol, and Cs₂CO₃ in place of5-fluoro-2-nitrotoluene, phenol, and K₂CO₃ in step A, and using Pd/C inplace of Fe in step B, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate, 1-propanephosphonic anhydride, anddiisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using(R)-5-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,prop-2-enoyl prop-2-enoate and diisopropylethylamine. MS (ESI): masscalcd. for C₂₈H₃₀N₆O₄S, 546.7; m/z found, 547.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): δ 9.51 (s, 1H), 8.35 (d, J=5.5 Hz, 1H), 8.03 (d, J=4.0 Hz, 1H),6.73 (s, 1H), 6.64 (t, J=13.8 Hz, 1H), 6.39 (d, J=16.8 Hz, 1H), 6.30 (d,J=16.9 Hz, 1H), 6.05 (s, 1H), 5.73 (s, 1H), 5.41 (tt, J=6.3, 2.8 Hz,1H), 5.30 (s, 2H), 4.16-4.04 (m, 2H), 3.56 (s, 1H), 3.26 (s, 1H),2.16-1.91 (m, 5H), 1.82 (dtt, J=15.5, 9.0, 6.3 Hz, 5H), 1.71-1.58 (m,3H), 1.26 (t, J=7.1 Hz, 1H).

Example 769:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H, (including chiral resolution Method A after step F to obtain the *Ratropisomer), in Example 1, and using 2-fluoro-4-methyl-5-nitropyridine,cyclopentanol, and Cs₂CO₃ in place of 5-fluoro-2-nitrotoluene, phenol,and K₂CO₃ in step A, and using Pd/C in place of Fe in step B, and usingtert-butyl (3R)-3-aminopiperidine-1-carboxylate, 1-propanephosphonicanhydride, and diisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using(R)-5-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,prop-2-enoyl prop-2-enoate and diisopropylethylamine. MS (ESI): masscalcd. for C₂₈H₃₀N₆O₄S, 546.7; m/z found, 547.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ 9.51 (s, 1H), 8.35 (d, J=5.5 Hz, 1H), 8.03-7.29 (m, 2H), 6.68(d, J=33.7 Hz, 2H), 6.39-6.05 (d, J=5.7 Hz, 3H), 5.74 (d, J=5.7 Hz, 1H),5.52-5.19 (m, 1H), 4.40-3.95 (m, 3H), 3.48-3.26 (m, 2H), 2.16-1.91 (m,5H), 1.82 (dtt, J=15.5, 9.0, 6.3 Hz, 5H), 1.71-1.58 (m, 3H), 1.26 (t,J=7.1 Hz, 1H).

Example 770:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-G, in Example 1, and using2-fluoro-5-nitro-6-picoline, tetrahydro-4-pyranol, acetonitrile, andCs₂CO₃ in place of 5-fluoro-2-nitrotoluene, phenol, DMF, and K₂CO₃ instep A, and using Pd/C in place of Fe in step B, and using1-[(3R)-3-amino-1-piperidyl]prop-2-en-1-one (Intermediate 15), PYOXIM,and diisopropylethylamine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G, to give the title compound. MS (ESI): masscalcd. for C₂₈H₃₀N₆O₅S, 562.6; m/z found, 563.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.34 (d, J=5.6 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 6.86-6.72 (m,2H), 6.20 (d, J=16.9 Hz, 1H), 6.11 (d, J=5.5 Hz, 1H), 5.82-5.70 (m, 1H),5.38-5.30 (m, 1H), 4.59-4.27 (m, 1H), 4.22-3.94 (m, 4H), 3.68-3.60 (m,2H), 3.23-3.13 (m, 1H), 3.01-2.84 (m, 1H), 2.27 (s, 3H), 2.15-2.04 (m,3H), 1.92-1.70 (m, 4H), 1.65-1.52 (m, 1H).

Example 771:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using 4-fluoronitrobenzene and2-methylpyridin-3-ol in place of 5-fluoro-2-nitrotoluene and phenol instep A, and using Pd/C in place of Fe, EtOH/H₂O, and NH₄Cl in step B,and using 4-((2-methylpyridin-3-yl)oxy)aniline in place of2-methyl-4-phenoxyaniline in step C, and using(R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₉H₂₆N₆O₄S,554.6; m/z found, 555.2 [M+H]+. ¹H NMR (400 MHz, CD₃OD): δ 8.35-8.23 (m,2H), 7.50-7.41 (m, 3H), 7.36-7.30 (m, 1H), 7.20-7.14 (m, 2H), 6.85-6.73(m, 1H), 6.23-6.15 (m, 2H), 5.79-5.67 (m, 1H), 4.56-4.27 (m, 1H),4.20-3.90 (m, 2H), 3.21-3.11 (m, 1H), 2.97-2.79 (m, 1H), 2.51 (s, 3H),2.10-2.01 (m, 1H), 1.90-1.82 (m, 1H), 1.80-1.65 (m, 1H), 1.63-1.50 (m,1H).

Example 772:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((6-methylpyridin-2-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using 4-amino-3-methylphenol and2-fluoro-6-methylpyridine in place of 5-fluoro-2-nitrotoluene and phenolin step A, and using 2-methyl-4-((6-methylpyridin-2-yl)oxy)aniline inplace of 2-methyl-4-phenoxyaniline in step C, and using(R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₀H₂₈N₆O₄S,568.6; m/z found, 569.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30 (d,J=5.5 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.46-7.34 (m, 1H), 7.21-7.14 (m,1H), 7.13-7.06 (m, 1H), 7.05-6.98 (m, 1H), 6.88-6.71 (m, 2H), 6.23-6.06(m, 2H), 5.76-5.63 (m, 1H), 4.59-4.28 (m, 1H), 4.25-3.86 (m, 2H),3.21-3.05 (m, 1H), 2.93-2.77 (m, 1H), 2.42 (s, 3H), 2.20-2.11 (m, 3H),2.09-1.98 (m, 1H), 1.90-1.80 (m, 1H), 1.77-1.48 (m, 2H).

Example 773:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using4-fluoro-2-methyl-1-nitrobenzene and 2-methylpyridin-3-ol in place of5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C in placeFe, EtOH/H₂O, and NH₄Cl in step B, and using2-methyl-4-((2-methylpyridin-3-yl)oxy)aniline in place of2-methyl-4-phenoxyaniline in step C, and using(R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₀H₂₈N₆O₄S,568.6; m/z found, 569.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35-8.30 (m,1H), 8.29-8.22 (m, 1H), 7.51-7.43 (m, 1H), 7.38-7.29 (m, 2H), 7.10-7.03(m, 1H), 7.00-6.93 (m, 1H), 6.86-6.72 (m, 1H), 6.24-6.14 (m, 1H),6.12-6.04 (m, 1H), 5.78-5.68 (m, 1H), 4.57-4.25 (m, 1H), 4.20-3.90 (m,2H), 3.22-3.11 (m, 1H), 3.02-2.80 (m, 1H), 2.51 (s, 3H), 2.14 (s, 3H),2.10-2.02 (m, 1H), 1.91-1.81 (m, 1H), 1.80-1.65 (m, 1H), 1.64-1.51 (m,1H).

Example 774:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using 4-fluoronitrobenzene and3-hydroxypyridine in place of 5-fluoro-2-nitrotoluene and phenol in stepA, and using Pd/C in place of Fe and NH₄Cl in step B, and using1-[(3R)-3-Amino-1-piperidyl]prop-2-en-1-one (Intermediate 15),1-propanephosphonic anhydride, DCM, and diisopropylethylamine in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU,DMF, and triethylamine in step G. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₄S,540.6; m/z found, 541.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): δ 10.18 (s,1H), 8.50 (d, J=2.7 Hz, 1H), 8.44 (dd, J=4.6, 1.3 Hz, 1H), 8.34 (d,J=5.5 Hz, 1H), 8.16-8.02 (m, 1H), 7.62-7.58 (m, 1H), 7.53-7.48 (m, 3H),7.26 (d, J=9.0 Hz, 2H), 6.86-6.72 (m, 1H), 6.14-6.08 (m, 2H), 5.69 (d,J=10.5 Hz, 1H), 4.53-4.15 (m, 1H), 4.07-3.99 (m, 1H), 3.84-3.76 (m, 1H),3.16-2.96 (m, 1H), 2.83-2.61 (m, 1H), 1.97-1.92 (m, 1H), 1.83-1.75 (m,1H), 1.74-1.58 (m, 1H), 1.51-1.36 (m, 1H).

Example 775:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using 4-aminophenol and2-fluoro-6-methylpyridine in place of 5-fluoro-2-nitrotoluene and phenolin step A, and no step B, and using 4-((6-methylpyridin-2-yl)oxy)anilinein place of 2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-Amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₉H₂₆N₆O₄S,554.6; m/z found, 555.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35 (d,J=5.6 Hz, 1H), 7.83-7.71 (m, 1H), 7.57-7.46 (m, 2H), 7.39-7.28 (m, 2H),7.13-7.02 (m, 1H), 6.91-6.70 (m, 2H), 6.34-6.16 (m, 2H), 5.87-5.66 (m,1H), 4.66-3.86 (m, 3H), 3.27-3.13 (m, 1H), 3.04-2.79 (m, 1H), 2.47 (s,3H), 2.17-2.03 (m, 1H), 1.97-1.86 (m, 1H), 1.82-1.53 (m, 2H).

Example 776:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-H in Example 1 (including Chiral Resolution Method Aafter step F to obtain the *S atropisomer), and using2-fluoro-4-methyl-5-nitropyridine and cyclopentanol in place of5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C in place ofFe and NH₄Cl in step B, and using (R)-tert-butyl3-aminopyrrolidine-1-carboxylate, diisopropylethylamine, DCM, and1-propanephosphonic anhydride in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, triethylamine, HATU,and DMF in step G.

Step B:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using(R)-5-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,acrylic anhydride and diisopropylethylamine. MS (ESI): mass calcd. forC₂₇H₂₈N₆O₄S, 532.6; m/z found, 533.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ9.69 (s, 1H), 8.32 (ddd, J=5.2, 4.0, 0.8 Hz, 1H), 8.05 (d, J=4.2 Hz,1H), 6.73 (s, 1H), 6.49-6.29 (m, 2H), 6.03 (dd, J=6.4, 5.5 Hz, 1H), 5.69(ddd, J=19.3, 9.7, 2.5 Hz, 1H), 5.41 (td, J=5.9, 5.4, 2.8 Hz, 1H), 5.31(s, 2H), 4.79-4.64 (m, 1H), 3.84-3.56 (m, 4H), 3.46 (d, J=0.9 Hz, 1H),2.19 (s, 3H), 2.03-1.90 (m, 2H), 1.90-1.73 (m, 4H), 1.64 (dtq, J=7.7,5.4, 2.8, 2.1 Hz, 2H).

Example 777:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(5-(2-fluorophenoxy)pyridin-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using 5-bromo-2-nitropyridine and2-fluorophenol in place of 5-fluoro-2-nitrotoluene and phenol in step A,and using Pd/C and MeOH in place of Fe, EtOH/H₂O, and NH₄Cl in step B,and using 5-(2-fluorophenoxy)pyridin-2-amine in place of2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-Amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₃FN₆O₄S,558.6; m/z found, 559.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.42-8.39 (m,1H), 8.35 (d, J=5.6 Hz, 1H), 7.67-7.56 (m, 2H), 7.42-7.25 (m, 4H),6.89-6.72 (m, 1H), 6.27-6.16 (m, 2H), 5.81-5.67 (m, 1H), 4.57-4.31 (m,1H), 4.21-3.91 (m, 2H), 3.24-3.14 (m, 1H), 2.98-2.85 (m, 1H), 2.12-2.02(m, 1H), 1.95-1.83 (m, 1H), 1.81-1.67 (m, 1H), 1.65-1.53 (m, 1H).

Example 778:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using 2-fluoropyridine and4-amino-3-methylphenol in place of 5-fluoro-2-nitrotoluene and phenol instep A, and no step B, and using 2-methyl-4-(pyridin-2-yloxy)aniline inplace of 2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-Amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₉H₂₆N₆O₄S,554.6; m/z found, 555.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34 (d,J=5.5 Hz, 1H), 8.21-8.13 (m, 1H), 7.92-7.83 (m, 1H), 7.43-7.34 (m, 1H),7.24-7.19 (m, 1H), 7.18-7.11 (m, 2H), 7.09-7.04 (m, 1H), 6.89-6.71 (m,1H), 6.26-6.13 m, 2H), 5.77-5.68 (m, 1H), 4.56-4.25 (m, 1H), 4.20-3.89(m, 2H), 3.25-3.11 (m, 1H), 3.01-2.82 (m, 1H), 2.17 (s, 3H), 2.12-2.02(m, 1H), 1.92-1.83 (m, 1H), 1.79-1.69 (m, 1H), 1.65-1.50 (m, 1H).

Example 779:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1 (including Chiral Resolution Method A after step F toobtain the *S atropisomer), and using 2-fluoro-4-methyl-5-nitropyridineand 2-methyl-1-propanol 5-fluoro-2-nitrotoluene and phenol in step A,and using Pd/C and MeOH in place of Fe, EtOH/H₂O, and NH₄Cl in step B,and using 6-isobutoxy-4-methylpyridin-3-amine in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using(R)-5-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,acrylic anhydride and diisopropylethylamine. MS (ESI): mass calcd. forC₂₆H₂₈N₆O₄S, 520.6; m/z found, 521.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ9.69 (s, 1H), 8.33 (dd, J=5.5, 4.0 Hz, 1H), 8.03 (d, J=4.2 Hz, 1H), 7.65(d, J=6.5 Hz, 1H), 6.80 (s, 1H), 6.50-6.33 (m, 2H), 6.03 (t, J=5.8 Hz,1H), 5.70 (ddd, J=14.0, 8.8, 3.5 Hz, 1H), 3.81-3.63 (m, 7H), 2.18-2.01(m, 6H), 1.03 (dd, J=6.6, 1.1 Hz, 6H).

Example 780:N¹-(15-Oxo-19-((3aR,4R,6aS)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)-N⁵-((E)-4-oxo-4-(3-(4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)but-2-en-1-yl)glutaramide

Step A:(R)-4-Oxo-5-(5-phenoxypyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-H in Example 1, and using 5-bromo-2-nitropyridine inplace of 5-fluoro-2-nitrotoluene in step A, and using Pd/C in place ofFe and NH₄Cl in step B, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B: (E)-4-((tert-Butoxycarbonyl)amino)but-2-enoic acid

To a round bottom flask containing (E)-4-aminobut-2-enoic acid (612 mg,6.05 mmol) was added (Boc)₂O (2.643 g, 12.11 mmol), Na₂CO₃ (1.674 g,12.11 mmol), THF (30 mL), and water (15 mL) and was stirred at rtovernight. The mixture was adjusted to pH=9 with aqueous LiOH andextracted with EtOAc. The aqueous layer was adjusted to pH=3 with 1 Maqueous HCl and was extracted with EtOAc. The organic layer wascollected and concentrated to dryness to give the title compound (1.10g, 90.3% yield), which was used in the next step without furtherpurification.

Step C:(R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-4-oxo-5-(5-phenoxypyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(187 mg, 0.358 mmol), (E)-4-((tert-butoxycarbonyl)amino)but-2-enoic acid(72.0 mg, 0.358 mmol), HATU (163 mg, 0.429 mmol) and triethylamine (109mg, 1.07 mmol) in anhydrous DMF was stirred at rt for 20 min. Themixture was purified by flash column chromatography to give a yellowsolid. The solid was diluted in 6.0 M aqueous HCl and was stirred at rtfor 10 min, then concentrated to dryness to give the title compound (156mg, 67.9% yield) as a yellow solid. MS (ESI): mass calcd. forC₂₉H₂₇N₇O₄S, 569.63; m/z found, 570.3 [M+H]⁺.

Step D: tert-Butyl(3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)carbamate

To a solution of3,3′-((oxybis(ethane-2,1-diyl))bis(oxy))bis(propan-1-amine) (10 g, 45mmol) and triethylamine (4.6 g, 45 mmol) in DCM (150 mL) was addedsolution of (Boc)₂O (5.0 g, 23 mmol) in DCM (100 mL) cooled in anice-bath and was stirred at rt overnight. The solution was concentratedto dryness and purified by flash column chromatography to give the titlecompound (5.976 g, 82.00% yield) as a slight yellow oil. MS (ESI): masscalcd. for C₁₅H₃₂N₂O₅, 320.42; m/z found, 321.2 [M+H]⁺.

Step E: tert-Butyl(15-oxo-19-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)carbamate

A solution of5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoicacid (4.0 g, 16 mmol), HATU (7.5 g, 20 mmol), and triethylamine (3.3 g,33 mmol) in anhydrous DMF (50 mL) was stirred at rt for 10 min.tert-Butyl (3-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)propyl)carbamate(5.976 g, 18.65 mmol) was added and the mixture was stirred for 16 h.The reaction was concentrated to dryness and purified by flash columnchromatography to give the title compound (5.8 g, 65% yield). MS (ESI):mass calcd. for C₂₅H₄₆N₄O₇S, 546.72; m/z found, 547.4 [M+H]⁺.

Step F:N-(3-(2-(2-(3-Aminopropoxy)ethoxy)ethoxy)propyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide

A solution of tert-butyl(15-oxo-19-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)carbamate(5.8 g, 11 mmol) in 5 M HCl in MeOH (30 mL) was concentrated to drynessat 50° C. to give the title compound (5.2 g, 100% yield) as a yellowoil. MS (ESI): mass calcd. for C₂₀H₃₈N₄O₅S, 446.61; m/z found, 447.3[M+H]⁺.

Step G: Methyl5,21-dioxo-25-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-10,13,16-trioxa-6,20-diazapentacosan-1-oate

A solution of 5-methoxy-5-oxopentanoic acid (1.57 g, 10.8 mmol), HATU(4.91 g, 12.9 mmol), and triethylamine (4.35 g, 43.1 mmol) in anhydrousDMF (50 mL) was stirred at rt for 10 min.N-(3-(2-(2-(3-Aminopropoxy)ethoxy)ethoxy)propyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide(5.2 g, 11 mmol) was added and the mixture was stirred for 16 h. Thereaction was concentrated to dryness and purified by flash columnchromatography to give the titled compound (3.3 g, 53% yield). MS (ESI):mass calcd. for C₂₆H₄₆N₄O₈S, 574.73; m/z found, 575.3 [M+H]⁺.

Step H:5,21-Dioxo-25-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-10,13,16-trioxa-6,20-diazapentacosan-1-oicacid

To a solution of methyl5,21-dioxo-25-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-10,13,16-trioxa-6,20-diazapentacosan-1-oate(3.3 g, 5.7 mmol) and CaCl₂ (9.6 g, 86 mmol) in iPrOH:H₂O (7:3, 108 mL)was added 0.5 M NaOH (14 mL) at rt. After 5 h, the reaction wasneutralized with 5 M aqueous HCl, extracted with DCM (3×100 mL), driedover anhydrous Na₂SO₄, and concentrated to dryness. The residue waspurified by flash column chromatography to give the titled compound (2.0g, 42% yield) as a colorless viscous foam. MS (ESI): mass calcd. forC₂₅H₄₄N₄O₈S, 560.70; m/z found, 561.3 [M+H]⁺.

Step I:N¹-(15-Oxo-19-((3aR,4R,6aS)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)-N⁵-((E)-4-oxo-4-(3-(4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)but-2-en-1-yl)glutaramide

A solution of5,21-dioxo-25-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-10,13,16-trioxa-6,20-diazapentacosan-1-oicacid (230 mg, 0.41 mmol), HATU (156 mg, 0.411 mmol), and triethylamine(55 mg, 0.55 mmol) in anhydrous DMF (10 mL) was stirred at rt for 10min.(R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(156 mg, 0.411 mmol) was added and the reaction was stirred for 2 h. Thereaction was concentrated to dryness and purified by flash columnchromatography to give the titled compound (102 mg, 33.2% yield) as alight yellow solid. MS (ESI): mass calcd. for C₅₄H₆₉N₁₁O₁₁S₂, 1112.3;m/z found, 1112.6 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.37 (s, 1H), 8.31(d, J=5.1 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.67-7.54 (m, 2H), 7.49-7.40(m, 1H), 7.20-7.12 (m, 2H), 6.75-6.64 (m, 1H), 6.61-6.48 (m, 1H), 6.23(d, J=4.8 Hz, 1H), 4.51-4.40 (m, 1H), 4.32-4.10 (m, 2H), 3.99-3.85 (m,3H), 3.63-3.42 (m, 12H), 3.27-3.10 (m, 6H), 2.96-2.82 (m, 2H), 2.72-2.62(m, 1H), 2.32-2.12 (m, 6H), 2.10-2.00 (m, 1H), 1.94-1.80 (m, 3H),1.79-1.46 (m, 11H), 1.46-1.34 (m, 2H).

Example 781:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using 2-fluoropyridine and4-amino-3-methylphenol in place of 5-fluoro-2-nitrotoluene and phenol instep A, and no step B, and using 2-methyl-4-(pyridin-2-yloxy)aniline inplace of 2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate 5) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₄S,540.6; m/z found, 541.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34 (d,J=5.5 Hz, 1H), 8.19-8.15 (m, 1H), 7.93-7.82 (m, 1H), 7.43-7.34 (m, 1H),7.25-7.20 (m, 1H), 7.18-7.10 (m, 2H), 7.10-7.04 (m, 1H), 6.67-6.53 (m,1H), 6.32-6.19 (m, 2H), 5.79-5.69 (m, 1H), 4.67-4.60 (m, 1H), 4.03-3.50(m, 4H), 2.38-2.23 (m, 1H), 2.17 (s, 3H), 2.16-2.01 (m, 1H).

Example 782:(R,EZ)—N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

Step A:(R)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 98) (300 mg, 0.601 mmol), 2-cyanoacetic acid (102 mg, 1.20mmol), HATU (297 mg, 0.780 mmol), and diisopropylethylamine (155 mg,1.20 mmol) in DMF (5 mL) was stirred at rt for 1 h. The mixture waspurified by flash column chromatography to give the title compound (225mg, 66.2% yield) as a white solid. MS (ESI): mass calcd. forC₃₀H₂₆N₆O₄S, 566.63; m/z found, 567.2 [M+H]+.

Step B:(R,EZ)—N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(70.0 mg, 0.124 mmol), 3-methyloxetane-3-carbaldehyde (37 mg, 0.37mmol), piperidine (0.30 mL), AcOH (0.10 mL), dioxane (5 mL), and 4Amolecular sieves (0.3 g) was stirred at 100° C. for 0.5 h under N₂. Themixture was concentrated to dryness and purified by flash columnchromatography to give the title compound as the E/Z mixture (55 mg, 68%yield) as white solid. MS (ESI): mass calcd. for C₃₅H₃₂N₆O₅S, 648.7; m/zfound, 649.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34-8.28 (m, 1H),7.44-7.36 (m, 2H), 7.34-6.79 (m, 2H), 7.19-7.12 (m, 1H), 7.11-7.02 (m,3H), 7.00-6.93 (m, 1H), 6.08-6.03 (m, 1H), 5.02-4.89 (m, 1H), 4.75-3.55(m, 8H), 2.17-2.01 (m, 4H), 1.98-1.84 (m, 1H), 1.80-1.56 (m, 4H),1.43-1.35 (m, 1H).

Example 783:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using4-fluoro-2-methyl-1-nitrobenzene and 6-methylpyridin-3-ol in place of5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C and MeOH inplace of Fe, EtOH/H₂O, and NH₄Cl in step B, and using2-methyl-4-((6-methylpyridin-3-yl)oxy)aniline in place of2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-Amino-1-piperidyl]prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₀H₂₈N₆O₄S,568.6; m/z found, 569.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32 (d,J=5.6 Hz, 1H), 8.29-8.19 (m, 1H), 7.53-7.45 (m, 1H), 7.39-7.30 (m, 2H),7.17-7.07 (m, 1H), 7.05-6.95 (m, 1H), 6.86-6.68 (m, 1H), 6.26-6.14 (m,1H), 6.07 (d, J=5.7 Hz, 1H), 5.78-5.66 (m, 1H), 4.58-4.23 (m, 1H),4.20-3.90 (m, 2H), 3.23-3.11 (m, 1H), 2.98-2.84 (m, 1H), 2.53 (s, 3H),2.14 (s, 3H), 2.10-2.03 (m, 1H), 1.92-1.81 (m, 1H), 1.79-1.66 (m, 1H),1.63-1.52 (m, 1H).

Example 784:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using 3,6-dichloropyridazine and3-methyl-4-nitrophenol in place of 5-fluoro-2-nitrotoluene and phenol instep A, and using Pd/C and MeOH in place of Fe, EtOH/H₂O, and NH₄Cl instep B, and using 2-methyl-4-(pyridazin-3-yloxy)aniline in place of2-methyl-4-phenoxyaniline in step C, and using(R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₅N₇O₄S,555.6; m/z found, 556.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆): δ8.97-8.93 (m, 1H), 8.33-8.28 (m, 1H), 7.74-7.68 (m, 1H), 7.46-7.38 (m,2H), 7.31-7.27 (m, 1H), 7.23-7.17 (m, 1H), 6.78-6.68 (m, 1H), 6.15-6.01(m, 2H), 5.69-5.61 (m, 1H), 4.51-4.01 (m, 2H), 3.88-3.78 (m, 1H),3.12-2.97 (m, 1H), 2.85-2.66 (m, 1H), 2.11 (s, 3H), 2.01-1.90 (m, 1H),1.83-1.72 (m, 1H), 1.71-1.56 (m, 1H), 1.55-1.41 (m, 1H).

Example 785:N—((R)-1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using4-fluoro-2-methyl-1-nitrobenzene and (S)-tetrahydrofuran-3-ol in placeof 5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C andMeOH/THF (2:1) in place of Fe, EtOH/H₂O, and NH₄Cl in step B, and using(S)-2-methyl-4-((tetrahydrofuran-3-yl)oxy)aniline in place of2-methyl-4-phenoxyaniline in step C, and using(R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₉N₅O₅S,547.6; m/z found, 548.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30 (d,J=5.6 Hz, 1H), 7.30-7.19 (m, 1H), 7.01-6.96 (m, 1H), 6.96-6.88 (m, 1H),6.85-6.73 (m, 1H), 6.24-6.11 (m, 1H), 6.02 (d, J=5.3 Hz, 1H), 5.78-5.66(m, 1H), 5.11-5.03 (m, 1H), 4.57-4.26 (m, 1H), 4.24-3.80 (m, 6H),3.22-3.09 (m, 1H), 2.95-2.82 (m, 1H), 2.33-2.21 (m, 1H), 2.18-2.09 (m,4H), 2.09-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.79-1.64 (m, 1H), 1.63-1.50(m, 1H).

Example 786:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-((5-methylpyridin-2-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using 1-fluoro-4-nitrobenzene and6-methylpyridin-3-ol in place of 5-fluoro-2-nitrotoluene and phenol instep A, and using Pd/C and MeOH in place of Fe, EtOH/H₂O, and NH₄Cl instep B, and using 4-((6-methylpyridin-3-yl)oxy)aniline in place of2-methyl-4-phenoxyaniline in step C, and using(R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₉H₂₆N₆O₄S,554.6; m/z found, 555.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.33-8.22 (m,2H), 7.53-7.40 (m, 3H), 7.37-7.30 (m, 1H), 7.26-7.17 (m, 2H), 6.84-6.69(m, 1H), 6.22-6.13 (m, 2H), 5.78-5.64 (m, 1H), 4.55-4.26 (m, 1H),4.23-3.88 (m, 2H), 3.25-3.08 (m, 1H), 2.97-2.79 (m, 1H), 2.52 (s, 3H),2.09-1.99 (m, 1H), 1.90-1.82 (m, 1H), 1.77-1.64 (m, 1H), 1.61-1.50 (m,1H).

Example 787:N—((R)-1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using4-fluoro-2-methyl-1-nitrobenzene and (R)-tetrahydrofuran-3-ol in placeof 5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C in placeFe, EtOH/H₂O, and NH₄Cl in step B, and using(R)-2-methyl-4-((tetrahydrofuran-3-yl)oxy)aniline in place of2-methyl-4-phenoxyaniline in step C, and using(R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₈H₂₉N₅O₅S,547.6; m/z found, 548.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30 (d,J=5.5 Hz, 1H), 7.33-7.19 (m, 1H), 7.04-6.97 (m, 1H), 6.96-6.90 (m, 1H),6.88-6.69 (m, 1H), 6.27-6.14 (m, 1H), 6.02 (d, J=5.5 Hz, 1H), 5.80-5.65(m, 1H), 5.15-5.04 (m, 1H), 4.63-4.24 (m, 1H), 4.21-3.80 (m, 6H),3.24-3.11 (m, 1H), 3.00-2.81 (m, 1H), 2.37-2.23 (m, 1H), 2.20-2.01 (m,5H), 1.93-1.83 (m, 1H), 1.82-1.67 (m, 1H), 1.65-1.52 (m, 1H).

Example 16:1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide

Step A: tert-Butyl(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)carbamate

5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27, 200 mg, 0.479 mmol) was heated under reflux inredistilled thionyl chloride (0.50 mL) for 5 h. The thionyl chloride wasremoved under reduced pressure and the residue was taken up in dryacetone (2 mL), cooled to 0° C., and sodium azide (500 mg, 7.69 mmol)was added dropwise with stirring and the solution was allowed to warm to20° C. over 10 min. The reaction was diluted with water, extracted withEtOAc, and the solvent was removed under reduced pressure. The residuewas taken up into t-butyl alcohol (37.5 mL) and was heated at reflux for5 h. The reaction was concentrated to dryness to give the title compound(180 mg, 53.9% yield). MS (ESI): mass calcd. for C₂₆H₂₄N₄O₄S, 488.56;m/z found, 489.0 [M+H]⁺.

Step B:1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide

The title compound was prepared usingN-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide(Example 828), acrylic acid, HATU, and diisopropylethylamine. MS (ESI):mass calcd. for C₃₀H₂₇N₅O₄S, 553.6; m/z found, 554.2 [M+H]⁺.

Example 789:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-H in Example 1 (including Chiral Resolution Method Aafter step F to obtain the *S atropisomer), and using2-fluoro-4-methyl-5-nitropyridine and 2-propanol in place of5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C in place ofFe and NH₄Cl in step B, and using (R)-1-Boc-3-aminopiperidine,1-propanephosphonic anhydride, and diisopropylethylamine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using(R)-5-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,acrylic anhydride and diisopropylethylamine. MS (ESI): mass calcd. forC₂₆H₂₈N₆O₄S, 520.6; m/z found, 521.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ8.35 (d, J=5.5 Hz, 1H), 8.01 (s, 1H), 6.72 (s, 1H), 6.63 (dd, J=16.7,10.6 Hz, 1H), 6.41 (s, 1H), 6.31 (d, J=17.5 Hz, 1H), 6.05 (d, J=5.5 Hz,1H), 5.95 (s, 1H), 5.73 (s, 1H), 5.38-5.26 (m, 1H), 4.05 (s, 1H),3.83-3.79 (m, 1H), 3.56 (s, 1H), 3.52-3.44 (m, 1H), 3.28 (s, 1H), 2.14(s, 3H), 2.07 (d, J=23.7 Hz, 1H), 2.00 (s, 1H), 1.71-1.62 (m, 1H), 1.37(dd, J=13.2, 6.2 Hz, 6H), 1.23 (dt, J=26.2, 7.1 Hz, 1H).

Example 790:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using 4-amino-3-methylphenol and3,6-dichloropyridazine in place of 5-fluoro-2-nitrotoluene and phenol instep A, and using Pd/C and MeOH in place of Fe, EtOH/H₂O, and NH₄Cl instep B, and using 2-methyl-4-(pyridazin-3-yloxy)aniline in place of2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate 5) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₃N₇O₄S,541.6; m/z found, 542.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.37 (s,1H), 9.06-9.01 (m, 1H), 8.42-8.31 (m, 2H), 7.83-7.76 (s, 1H), 7.56-7.50(m, 1H), 7.49-7.43 (m, 1H), 7.36-7.32 (m, 1H), 7.28-7.22 (m, 1H),6.65-6.51 (m, 1H), 6.18-6.09 (m, 1H), 6.00-5.94 (m, 1H), 5.70-5.62 (m,1H), 4.58-4.40 (m, 1H), 3.90-3.40 (m, 4H), 2.24-1.95 (m, 5H).

Example 791:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using 3,6-dichloropyridazine and4-nitrophenol in place of 5-fluoro-2-nitrotoluene and phenol in step A,and using Pd/C and MeOH in place of Fe, EtOH/H₂O, and NH₄Cl in step B,and using 4-(pyridazin-3-yloxy)aniline in place of2-methyl-4-phenoxyaniline in step C, and using(R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₃N₇O₄S,541.6; m/z found, 542.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.98-8.94 (m,1H), 8.35-8.31 (m, 1H), 7.81-7.75 (m, 1H), 7.55-7.48 (m, 3H), 7.47-7.42(m, 2H), 6.85-6.73 (m, 1H), 6.34-6.19 (m, 1H), 6.24-6.16 (m, 1H),5.77-5.69 (m, 1H), 4.55-4.27 (m, 1H), 4.21-3.90 (m, 2H), 3.24-3.10 (m,1H), 3.00-2.82 (m, 1H), 2.17-1.99 (m, 1H), 1.94-1.83 (m, 1H), 1.79-1.66(m, 1H), 1.65-1.53 (m, 1H).

Example 792:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutyl-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 6-Isobutyl-2-methylpyridin-3-amine

To a 500 mL round bottom flask were added 5-amino-2-bromo-6-picoline(5.0 g, 27 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (550 mg, 0.668 mmol), and THF (27 mL) withstirring. The flask was evacuated, then refilled with N₂ (3×). Next wasadded 2-methylpropylzinc bromide (0.5 M in THF, 27 mL, 27 mmol) and washeated to 60° C. for 3 h.

The reaction was cooled in an ice bath and NaHCO₃ was added to quenchthe reaction. The reaction was extracted with DCM, washed with water andbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated todryness. The residue was purified by normal phase flash columnchromatography (SiO₂) to give the title compound (2.46 g, 56.0% yield)as a beige solid.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutyl-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps C-G in Example 1, and using6-isobutyl-2-methylpyridin-3-amine in place of 2-methyl-4-phenoxyanilinein step C, and using (R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one(Intermediate 15) in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. Atropisomers were resolved by chiral SFC (Stationary phase:CHIRALCEL AS-H, 5 m, 250×20 mm, Mobile phase: 65% CO₂, 35% MeOH), togive the title compound. MS (ESI): mass calcd. for C₂₇H₃₀N₆O₃S, 518.6;m/z found, 519.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆): δ 10.31 (s, 1H),8.34 (d, J=5.5 Hz, 1H), 8.21-8.07 (m, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.29(d, J=8.0 Hz, 1H), 6.86-6.72 (m, 1H), 6.11 (d, J=16.8 Hz, 1H), 5.93 (d,J=5.5 Hz, 1H), 5.69 (d, J=10.3 Hz, 1H), 4.35 (dd, J=128.2, 12.2 Hz, 1H),4.03 (dd, J=39.6, 11.8 Hz, 1H), 3.79 (s, 1H), 3.05 (d, J=47.2, 12.1 Hz,1H), 2.81-2.62 (m, 3H), 2.28 (s, 3H), 2.17-2.06 (m, 1H), 1.98-1.92 (m,1H), 1.82-1.75 (m, 1H), 1.75-1.58 (m, 1H), 1.50-1.35 (m, 1H), 0.94 (d,J=6.6 Hz, 6H).

Example 793:(R)-5-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1 (including Chiral Resolution Method Aafter step F to obtain the *S atropisomer), and using6-chloro-2-methyl-3-nitropyridine in place of 5-fluoro-2-nitrotoluene instep A, and using Pd/C in place of Fe and NH₄Cl in step B, and using(R)-tetrahydrofuran-3-amine hydrochloride and diisopropylethylamine inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate andtriethylamine in step G. MS (ESI): mass calcd. for C₂₅H₂₁N₅O₄S, 487.5;m/z found, 488.0 [M+H]⁺. ¹H NMR (500 MHz, Methanol-d4) δ 8.36 (d, J=5.5Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.56-7.10 (m, 5H), 6.91 (d, J=8.6 Hz,1H), 6.15 (d, J=5.5 Hz, 1H), 4.66-4.52 (m, 1H), 4.11-3.67 (m, 4H),2.33-2.18 (m, 4H), 2.11-1.95 (m, 1H).

Example 794:(R)-5-(*S)-(6-Isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-H in Example 1 (including Chiral Resolution Method Aafter step F to obtain the *S atropisomer), and using2-fluoro-4-methyl-5-nitropyridine and 2-propanol in place of5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C in place ofFe and NH₄Cl in step B, and using (R)-1-Boc-3-aminopiperidine,1-propanephosphonic anhydride, and diisopropylethylamine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G. MS (ESI): mass calcd. for C₂₃H₂₆N₆O₃S, 466.6;m/z found, 467.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 8.34 (d, J=5.4 Hz,1H), 8.00 (s, 1H), 6.72 (s, 1H), 6.48 (s, 1H), 6.04 (d, J=5.5 Hz, 1H),5.38-5.26 (m, 1H), 4.18-4.13 (m, 3H), 3.48 (s, 1H), 3.10 (dd, J=11.8,3.2 Hz, 1H), 2.84 (dtq, J=24.2, 11.9, 6.1, 5.4 Hz, 3H), 2.13 (s, 3H),1.79 (dtdd, J=43.5, 12.8, 8.3, 4.1 Hz, 3H), 1.37 (dd, J=13.6, 6.2 Hz,6H).

Example 795:(S)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(S)-4-oxo-5-(5-phenoxypyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-H in Example 1, and using 5-bromo-2-nitropyridine inplace of 5-fluoro-2-nitrotoluene in step A, and using Pd/C in place ofFe and NH₄Cl in step B, and using (S)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(S)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using(S)-4-oxo-5-(5-phenoxypyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamideand acrylic anhydride. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₄S, 540.6; m/zfound, 541.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.37 (d, J=2.8 Hz, 1H),8.31 (d, J=5.6 Hz, 1H), 7.65-7.55 (m, 2H), 7.50-7.42 (m, 2H), 7.28-7.21(m, 1H), 7.20-7.14 (m, 2H), 6.84-6.72 (m, 1H), 6.24-6.14 (m, 2H),5.76-5.78 (m, 1H), 4.56-4.27 (m, 1H), 4.20-3.89 (m, 2H), 3.21-3.11 (m,1H), 2.98-2.84 (m, 1H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.79-1.65(m, 1H), 1.63-1.50 (m, 1H).

Example 796:2-(4-Acryloylpiperazin-1-yl)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

Step A:5-(2-Methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

To a solution of5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) (7.0 g, 17 mmol) in 1-methyl-2-pyrrolidinone (70mL) were added silver acetate (559 mg, 3.35 mmol) and potassiumcarbonate (695 mg, 5.03 mmol) and was stirred at 120° C. for 30 min. Thereaction was filtered and concentrated to dryness. The residue waspurified by FFC to give the title compound (6.0 g, 96% yield).

Step B:2-Chloro-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

To a solution of5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one(4.5 g, 12 mmol) in CHCl₃ (30 mL) was added N-chlorosuccinimide (1.61 g,12.1 mmol) and was stirred for 30 min at room temperature. The reactionwas concentrated to dryness and methanol was added to the residue, thesolution filtered, the precipitate washed with methanol, and dried underhigh vacuum to give the title compound (3.5 g, 71% yield). MS (ESI):mass calcd. for C₂₁H₁₄ClN₃O₂S, 408.87; m/z found, 407.9 [M+H]⁺.

Step C: tert-Butyl4-(5-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperazine-1-carboxylate

To a solution of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27, 700 mg, 1.72 mmol) in DMSO (5 mL) were added1-Boc-piperazine (3.20 g, 17.2 mmol), Cu (22 mg, 0.34 mmol), copper(I)iodide (65 mg, 0.34 mmol), and potassium phosphate (1.09 g, 5.15 mmol).The reaction mixture was irradiated in a microwave at 120° C. for 2.5 h.The reaction was poured into citric acid (100 mL, 4 M in water) andextracted with DCM (3×60 mL). The combined organic layers concentratedto dryness and the residue was purified by preparative reverse phaseC-18 HPLC to give the title compound (600 mg, 63% yield).

Step D:5-(2-Methyl-4-phenoxyphenyl)-2-(piperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

To a solution of tert-butyl4-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperazine-1-carboxylate(600 mg, 1.08 mmol) in EtOAc (5 mL) was added saturated aqueous HCl (5mL) and was stirred for 3 h at room temperature. The mixture was pouredinto aqueous NaHCO₃ (50 mL) and extracted with DCM (3×30 mL). Thecombined organic layers were washed with saturated brine (50 mL), driedover anhydrous Na₂SO₄, filtered, and concentrated to dryness. Theresidue was purified by preparative reverse phase C18 HPLC to give thetitle compound (400 mg, 65% yield).

Step E:2-(4-Acryloylpiperazin-1-yl)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

To a solution of5-(2-methyl-4-phenoxyphenyl)-2-(piperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one(100 mg, 0.219 mmol), acrylic acid (19 mg, 0.26 mmol) anddiisopropylethylamine (0.153 mL, 0.876 mmol) in DCM (2 mL) at 0° C. wasadded HATU (125 mg, 0.329 mmol) and was stirred for 2 h at 20° C. Theorganic layer was washed with saturated aqueous NaHCO₃ (50 mL), driedover anhydrous Na₂SO₄, and concentrated to dryness. The residue waspurified by preparative HPLC to give the title compound (21.7 mg, 15.1%yield). MS (ESI): mass calcd. for C₂₈H₂₅N₅O₃S, 511.6; m/z found, 512.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.72 (s, 1H), 8.16 (d, J=5.5 Hz,1H), 7.48-7.42 (m, 2H), 7.35 (d, J=8.5 Hz, 1H), 7.23-7.17 (m, 1H),7.14-7.08 (m, 3H), 6.98 (dd, J=2.6, 8.4 Hz, 1H), 6.85 (dd, J=10.5, 16.6Hz, 1H), 6.15 (dd, J=2.4, 16.7 Hz, 1H), 5.85 (d, J=5.5 Hz, 1H), 5.72(dd, J=2.4, 10.4 Hz, 1H), 3.78-3.69 (m, 4H), 2.91-2.85 (m, 4H), 2.07 (s,3H).

Example 797:(R)-5-(*S)-(6-(Cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-H in Example 1 (including Chiral Resolution Method Aafter step F to obtain the *S atropisomer), and using2-fluoro-4-methyl-5-nitropyridine and cyclopentanol in place of5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C in place ofFe and NH₄Cl in step B, and using (R)-tert-butyl3-aminopyrrolidine-1-carboxylate, diisopropylethylamine, DCM, and1-propanephosphonic anhydride in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, triethylamine, HATU,and DMF in step G. MS (ESI): mass calcd. for C₂₄H₂₆N₆O₃S, 478.6; m/zfound, 479.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 9.57 (s, 3H), 8.27 (d,J=5.5 Hz, 1H), 8.03 (s, 1H), 7.92 (d, J=6.8 Hz, 1H), 6.69 (s, 1H), 5.98(d, J=5.5 Hz, 1H), 5.37 (dp, J=6.2, 2.7 Hz, 1H), 5.30 (s, 1H), 4.76 (d,J=13.8 Hz, 1H), 3.64-3.45 (m, 4H), 3.34 (dt, J=11.5, 7.8 Hz, 1H),2.42-2.33 (m, 1H), 2.22 (d, J=8.0 Hz, 1H), 2.10 (s, 3H), 1.95 (ddd,J=14.2, 11.3, 6.5 Hz, 2H), 1.83-1.73 (m, 1H), 1.63 (dtd, J=9.7, 7.6, 4.3Hz, 2H).

Example 798:(R)-5-(*S)-(6-Isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-H in Example 1 (including Chiral Resolution Method Aafter step F to obtain the *S atropisomer), and using2-fluoro-4-methyl-5-nitropyridine and 2-methyl-1-propanol in place of5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C in place ofFe and NH₄Cl in step B, and using (R)-tert-butyl3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₃H₂₆N₆O₃S, 466.6; m/z found, 467.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 8.31 (d, J=5.5 Hz, 1H), 8.02 (s, 1H),7.71 (d, J=6.9 Hz, 1H), 6.77 (s, 1H), 6.01 (d, J=5.5 Hz, 1H), 5.30 (s,1H), 4.78 (s, 1H), 3.62-3.43 (m, 8H), 3.31 (dtd, J=11.4, 8.5, 7.7, 3.8Hz, 1H), 2.45-2.33 (m, 1H), 2.11 (s, 3H), 1.02 (dd, J=6.8, 1.6 Hz, 6H).

Example 799:(R)-5-(2-Methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A, and C-H in Example 1, and using 2-fluoropyridine and4-amino-3-methylphenol in place of 5-fluoro-2-nitrotoluene and phenol instep A, and using (R)-tert-butyl 3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)-5-(2-Methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using(R)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,propionic anhydride and DIPEA. MS (ESI): mass calcd. for C₂₉H₂₈N₆O₄S,556.6; m/z found, 557.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.35 (d,J=5.5 Hz, 1H), 8.22-8.13 (m, 1H), 7.94-7.83 (m, 1H), 7.42-7.34 (m, 1H),7.27-7.20 (m, 1H), 7.18-7.11 (m, 2H), 7.10-7.03 (m, 1H), 6.29-6.17 (m,1H), 4.52-4.30 (m, 1H), 4.10-3.82 (m, 2H), 3.15-2.99 (m, 1H), 2.84-2.68(m, 1H), 2.54-2.38 (m, 2H), 2.17 (s, 3H), 2.10-2.01 (m, 1H), 1.91-1.78(m, 1H), 1.75-1.48 (m, 2H), 1.18-1.07 (m, 3H).

Example 800:(R)—N-(1-Acetylpiperidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A, and C-H in Example 1, and using 2-fluoropyridine and4-amino-3-methylphenol in place of 5-fluoro-2-nitrotoluene and phenol instep A, and using (R)-tert-butyl 3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)—N-(1-Acetylpiperidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using(R)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,acetic anhydride and DIPEA. MS (ESI): mass calcd. for C₂₈H₂₆N₆O₄S,542.6; m/z found, 543.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.36-8.28 (m,1H), 8.19-8.11 (m, 1H), 7.90-7.81 (m, 1H), 7.45-7.35 (m, 1H), 7.24-7.17(m, 1H), 7.17-7.09 (m, 2H), 7.09-7.01 (m, 1H), 6.23-6.15 (m, 1H),4.54-4.26 (m, 1H), 4.08-3.78 (m, 2H), 3.19-3.01 (m, 1H), 2.81-2.65 (m,1H), 2.20-2.10 (m, 6H), 2.08-2.01 (m, 1H), 1.89-1.77 (m, 1H), 1.73-1.47(m, 2H).

Example 801:(E)-1-(2-Cyano-3-cyclopropylacryloyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide

The title compound was prepared using conditions analogous to Example877, and usingN-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide(Example 828) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889).

Example 802:1-Cyano-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide

The title compound was prepared using conditions analogous Example 890,and usingN-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide(Example 828) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889). MS (ESI): mass calcd. for C₂₈H₂₄N₆O₃S, 524.6; m/z found,525.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.25-10.22 (m, 1H), 10.13(s, 1H), 8.16 (d, J=5.3 Hz, 1H), 7.48-7.42 (m, 2H), 7.38-7.33 (m, 1H),7.23-7.17 (m, 1H), 7.14-7.07 (m, 3H), 6.98 (dd, J=2.8, 8.5 Hz, 1H), 5.86(d, J=5.5 Hz, 1H), 3.37-3.31 (m, 2H), 3.20-3.12 (m, 1H), 3.08-3.01 (m,1H), 2.07 (s, 3H), 2.03-1.97 (m, 1H), 1.78-1.71 (m, 1H), 1.64-1.56 (m,2H), 1.25-1.21 (m, 1H).

Example 803:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-G in Example 1, and using 3,6-dichloropyridazine and4-nitrophenol in place of 5-fluoro-2-nitrotoluene and phenol in step A,and using Pd/C and MeOH in place of Fe, EtOH/H₂O, and NH₄Cl in step B,and using 4-(pyridazin-3-yloxy)aniline in place of2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate 5) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₆H₂₁N₇O₄S,527.6; m/z found, 528.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD and DMSO-d₆(2:1)): δ 8.96-8.91 (m, 1H), 8.28-8.23 (m, 1H), 7.73-7.66 (m, 1H),7.50-7.42 (m, 3H), 7.40-7.34 (m, 2H), 6.61-6.47 (m, 1H), 6.20-6.13 (m,2H), 5.69-5.61 (m, 1H), 4.63-4.43 (m, 1H), 3.91-3.73 (m, 1H), 3.65-3.40(m, 3H), 2.25-1.96 (m, 2H).

Example 804:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-H in Example 1 (including Chiral Resolution Method Aafter step F to obtain the *R atropisomer), and using2-fluoro-4-methyl-5-nitropyridine and 2-propanol in place of5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C in place ofFe and NH₄Cl in step B, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate, 1-propanephosphonic anhydride,diisopropylethylamine, and DCM in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, triethylamine,and DMF in step G.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using(R)-5-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,acrylic anhydride. MS (ESI): mass calcd. for C₂₆H₂₈N₆O₄S, 520.6; m/zfound, 521.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 8.35 (d, J=5.5 Hz, 1H),8.02 (s, 1H), 6.67 (d, J=44.7 Hz, 2H), 6.39 (d, J=17.1 Hz, 1H), 6.31 (d,J=17.1 Hz, 1H), 6.14 (s, 1H), 6.08-6.03 (m, 1H), 5.72 (d, J=12.1 Hz,1H), 5.32 (p, J=6.2 Hz, 1H), 4.17-4.04 (m, 2H), 3.56 (s, 1H), 2.13 (s,3H), 2.05 (s, 2H), 1.65 (dd, J=12.8, 6.4 Hz, 1H), 1.37 (dd, J=13.2, 6.2Hz, 6H), 1.26 (t, J=7.2 Hz, 2H), 1.08-1.01 (m, 1H).

Example 805:N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)-1-propionylpiperidine-4-carboxamide

The title compound was prepared using conditions analogous to Example75, and usingN-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide(Example 833) and propionic acid in place of 3-hydroxypropanoic acid. MS(ESI): mass calcd. for C₃₀H₂₉N₅O₄S, 555.6; m/z found, 556.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 10.24 (s, 1H), 10.12 (s, 1H), 8.16 (d, J=5.5Hz, 1H), 7.49-7.41 (m, 2H), 7.36 (d, J=8.6 Hz, 1H), 7.22-7.18 (m, 1H),7.15-7.06 (m, 3H), 6.98 (dd, J=8.5, 2.8 Hz, 1H), 5.87 (d, J=5.5 Hz, 1H),4.47-4.39 (m, 1H), 3.97-3.89 (m, 1H), 3.12-3.04 (m, 1H), 2.70-2.54 (m,2H), 2.38-2.31 (m, 2H), 2.07 (s, 3H), 1.93-1.82 (m, 2H), 1.66-1.39 (m,2H), 1.00 (t, J=7.4 Hz, 3H).

Example 806:(R)-5-(*R)-(6-Isopropoxy-4-methylpyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-H in Example 1 (including Chiral Resolution Method Aafter step F to obtain the *R atropisomer), and using2-fluoro-4-methyl-5-nitropyridine and 2-propanol in place of5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C in place ofFe and NH₄Cl in step B, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate, 1-propanephosphonic anhydride,diisopropylethylamine, and DCM in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, triethylamine,and DMF in step G. MS (ESI): mass calcd. for C₂₃H₂₆N₆O₃S, 466.6; m/zfound, 467.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ 8.33 (d, J=5.5 Hz, 1H),8.03 (s, 1H), 6.72 (t, J=0.8 Hz, 1H), 6.46-6.41 (m, 1H), 6.03 (d, J=5.5Hz, 1H), 5.38-5.27 (m, 2H), 4.14 (ddp, J=9.3, 6.5, 3.4 Hz, 1H), 3.48 (s,1H), 3.08 (dd, J=11.9, 3.1 Hz, 1H), 2.90-2.75 (m, 3H), 2.12 (d, J=0.9Hz, 3H), 1.77 (dddd, J=28.7, 13.8, 11.3, 7.2 Hz, 3H), 1.57 (dtd, J=12.8,6.3, 5.7, 2.8 Hz, 1H), 1.37 (dd, J=13.5, 6.2 Hz, 6H).

Example 807:(R)-4-Oxo-N-(1-propionylpiperidin-3-yl)-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-4-oxo-N-(piperidin-3-yl)-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA, and C-H in Example 1, and using 2-fluoropyridine and 4-aminophenol inplace of phenol and 5-fluoro-2-nitrotoluene in step A, and using4-(pyridin-2-yloxy)aniline in place of 2-methyl-4-phenoxyaniline in stepC, and using (R)-tert-butyl 3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G.

Step B:(R)-4-Oxo-N-(1-propionylpiperidin-3-yl)-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

In a solution of(R)-4-oxo-N-(piperidin-3-yl)-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(200 mg) in DCM (5 mL) was added triethylamine (83 mg). The mixture wascooled in an ice bath, and propionic anhydride (80 mg) was added slowly.The solution was allowed to stir at rt for 15 min, then the mixture waspoured into water, extracted with DCM, and concentrated. The crudemixture was purified by ISCO (MeOH/H₂O), then preparative TLC (25/1DCM/MeOH) to yield the title compound (130 mg, 85% yield). MS (ESI):mass calcd. for C₂₈H₂₆N₆O₄S, 542.6; m/z found, 543.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.31 (d, J=5.5 Hz, 1H), 8.20-8.12 (m, 1H), 7.90-7.82 (m,1H), 7.52-7.44 (m, 2H), 7.35-7.28 (m, 2H), 7.19-7.11 (m, 1H), 7.10-7.02(m, 1H), 6.29 (d, J=5.5 Hz, 1H), 4.54-4.29 (m, 1H), 4.12-3.81 (m, 2H),3.14-2.96 (m, 1H), 2.79-2.65 (m, 1H), 2.55-2.34 (m, 2H), 2.09-1.96 (m,1H), 1.90-1.76 (m, 1H), 1.75-1.47 (m, 2H), 1.16-1.08 (m, 3H).

Example 808:(R)—N-(1-Acetylpiperidin-3-yl)-4-oxo-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA, C-I in Example 1, and using 2-fluoropyridine and 4-aminophenol inplace of phenol and 5-fluoro-2-nitrotoluene in step A, and using4-(pyridin-2-yloxy)aniline in place of 2-methyl-4-phenoxyaniline in stepC, and using (R)-tert-butyl 3-aminopiperidine-1-carboxylate in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, and using acetyl chloride in place ofprop-2-enoyl chloride in step I. MS (ESI): mass calcd. for C₂₇H₂₄N₆O₄S,528.6; m/z found, 529.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.29 (d,J=5.6 Hz, 1H), 8.18-8.12 (m, 1H), 7.90-7.82 (m, 1H), 7.49-7.43 (m, 2H),7.36-7.27 (m, 2H), 7.19-7.12 (m, 1H), 7.09-7.03 (m, 1H), 6.27 (d, J=5.6Hz, 1H), 4.52-4.23 (m, 1H), 4.09-3.76 (m, 2H), 3.18-3.01 (m, 1H),2.81-2.67 (m, 1H), 2.16-2.09 (m, 3H), 2.09-1.97 (m, 1H), 1.90-1.76 (m,1H), 1.74-1.48 (m, 2H).

Example 809:(R)-5-(2-Methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-45-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-H in Example 1, and using 4-amino-3-methylphenol and3,6-dichloropyridazine in place of 5-fluoro-2-nitrotoluene and phenol instep A, and using Pd/C in place of Fe and NH₄Cl in step B, and using(R)-tert-butyl 3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)-5-(2-Methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as Example 75and using(R)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamideand propionic anhydride in place of 3-hydroxypropanoic acid. MS (ESI):mass calcd. for C₂₈H₂₇N₇O₄S, 557.6; m/z found, 558.3 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.96-8.90 (m, 1H), 8.32-8.26 (m, 1H), 7.79-7.71 (m, 1H),7.52-7.42 (m, 2H), 7.32-7.27 (m, 1H), 7.27-7.20 (m, 1H), 6.19-6.14 (m,1H), 4.58-4.30 (m, 1H), 4.13-3.78 (m, 2H), 3.12-2.92 (m, 1H), 2.77-2.60(m, 1H), 2.51-2.32 (m, 2H), 2.20-2.12 (m, 3H), 2.07-1.95 (m, 1H),1.86-1.74 (m, 1H), 1.72-1.60 (m, 1H), 1.60-1.43 (m, 1H), 1.13-1.05 (m,3H).

Example 810:(R)—N-(1-Acetylpiperidin-3-yl)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-4-Oxo-N-(1-propionylpiperidin-3-yl)-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-H in Example 1, and using 4-amino-3-methylphenol and3,6-dichloropyridazine in place of 5-fluoro-2-nitrotoluene and phenol instep A, and using Pd/C in place of Fe and NH₄Cl in step B, and using(R)-tert-butyl 3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)—N-(1-Acetylpiperidin-3-yl)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example75, and using(R)-4-Oxo-N-(1-propionylpiperidin-3-yl)-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamideand acetic anhydride in place of 3-hydroxypropanoic acid. MS (ESI): masscalcd. for C₂₇H₂₅N₇O₄S, 543.6; m/z found, 544.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.96-8.90 (m, 1H), 8.32-8.26 (m, 1H), 7.79-7.71 (m, 1H),7.52-7.42 (m, 2H), 7.32-7.27 (m, 1H), 7.27-7.20 (m, 1H), 6.20-6.16 (m,1H), 4.56-4.27 (m, 1H), 4.10-3.76 (m, 2H), 3.12-2.99 (m, 1H), 2.79-2.66(m, 1H), 2.21-2.14 (m, 3H), 2.15-2.09 (m, 3H), 2.07-1.95 (m, 1H),1.91-1.74 (m, 1H), 1.71-1.61 (m, 1H), 1.61-1.43 (m, 1H).

Example 811:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-4-oxo-N-(piperidin-3-yl)-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-H in Example 1, and using 3,6-dichloropyridazine and4-nitrophenol in place of 5-fluoro-2-nitrotoluene and phenol in step A,and using Pd/C in place of Fe and NH₄Cl in step B, and using(R)-tert-butyl 3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inExample 75 and using(R)-4-oxo-N-(piperidin-3-yl)-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamideand propionic anhydride in place of 3-hydroxypropanoic acid. MS (ESI):mass calcd. for C₂₇H₂₅N₇O₄S, 543.6; m/z found, 544.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ 8.99-8.94 (m, 1H), 8.36-8.31 (m, 1H), 7.83-7.74 (m, 1H),7.59-7.49 (m, 3H), 7.47-7.38 (m, 2H), 6.36-6.29 (m, 1H), 4.55-4.33 (m,1H), 4.11-3.84 (m, 2H), 3.14-2.99 (m, 1H), 2.83-2.68 (m, 1H), 2.54-2.40(m, 2H), 2.13-2.00 (m, 1H), 1.94-1.77 (m, 1H), 1.76-1.52 (m, 2H),1.16-1.09 (m, 3H).

Example 812:(R)—N-(1-Acetylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-4-oxo-N-(piperidin-3-yl)-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps A-H in Example 1, and using 3,6-dichloropyridazine and4-nitrophenol in place of 5-fluoro-2-nitrotoluene and phenol in step A,and using Pd/C in place of Fe and NH₄Cl in step B, and using(R)-tert-butyl 3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G.

Step B:(R)—N-(1-Acetylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inExample 75 and using(R)-4-oxo-N-(piperidin-3-yl)-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamideand acetic anhydride in place of 3-hydroxypropanoic acid. MS (ESI): masscalcd. for C₂₆H₂₃N₇O₄S, 529.6; m/z found, 530.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.99-8.94 (m, 1H), 8.36-8.31 (m, 1H), 7.82-7.73 (m, 1H),7.57-7.48 (m, 3H), 7.47-7.38 (m, 2H), 6.36-6.28 (m, 1H), 4.55-4.29 (m,1H), 4.07-3.79 (m, 2H), 3.14-3.02 (m, 1H), 2.80-2.71 (m, 1H), 2.15-2.11(m, 3H), 2.08-2.00 (m, 1H), 1.88-1.76 (m, 1H), 1.75-1.51 (m, 2H).

Example 17:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-acryloylpiperidin-3-yl)-5-(2-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 770) was resolved by chiral SFC (Stationary phase: ChiralpakAS-H; 5 m, 250×20 mm, Mobile phase: 65% CO₂, 35% MeOH) to yield thetitle compound. MS (ESI): mass calcd. for C₂₈H₃₀N6O5S, 562.6; m/z found,563.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.28 (s, 1H), 8.35 (d, J=5.5Hz, 1H), 8.21-8.05 (m, 1H), 7.74 (d, J=8.6 Hz, 1H), 6.92-6.72 (m, 2H),6.20-6.01 (m, 2H), 5.82-5.64 (m, 1H), 5.30-5.18 (m, 1H), 4.57-4.20 (m,1H), 4.16-3.95 (m, 1H), 3.94-3.85 (m, 2H), 3.80 (s, 1H), 3.61-3.49 (m,2H), 3.15-2.93 (m, 1H), 2.83-2.62 (m, 1H), 2.21 (s, 3H), 2.12-2.02 (m,2H), 2.00-1.90 (m, 1H), 1.83-1.75 (m, 1H), 1.74-1.62 (m, 3H), 1.55-1.34(m, 1H).

Example 18:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 770) was resolved by chiral SFC (Stationary phase: ChiralpakAS-H; 5 μm, 250×20 mm, Mobile phase: 65% CO₂, 35% MeOH) to yield thetitle compound. MS (ESI): mass calcd. for C₂₈H₃₀N₆O₅S, 562.6; m/z found,563.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.29 (s, 1H), 8.34 (d, J=5.5Hz, 1H), 8.23-8.07 (m, 1H), 7.74 (d, J=8.6 Hz, 1H), 6.91-6.71 (m, 2H),6.12 (d, J=16.7 Hz, 1H), 6.04 (d, J=5.5 Hz, 1H), 5.69 (d, J=10.4 Hz,1H), 5.33-5.22 (m, 1H), 4.57-4.15 (m, 1H), 4.13-3.96 (m, 1H), 3.94-3.86(m, 2H), 3.84-3.73 (m, 1H), 3.54 (t, 2H), 3.21-2.92 (m, 1H), 2.87-2.61(m, 1H), 2.21 (s, 3H), 2.12-2.01 (m, 2H), 2.00-1.91 (m, 1H), 1.84-1.75(m, 1H), 1.74-1.61 (m, 3H), 1.53-1.37 (m, 1H).

Example 815:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutyl-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: 6-Isobutyl-2-methylpyridin-3-amine

To a 500 mL round bottom flask were added6-bromo-2-methylpyridin-3-amine (5.0 g, 27 mmol), a stir bar, and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (520 mg, 0.631 mmol) in THF (27 mL). The vesselwas evacuated then back filled with nitrogen (3×). Then isobutylzinc(II)bromide (75 mL, 37 mmol) was added via syringe and the reaction washeated to 60° C. for 3 h. The reaction was treated with saturatedaqueous sodium bicarbonate, extracted with DCM, the organic phase washedwith water and brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was purified by normal phase flashcolumn chromatography (SiO₂) to give the title compound (2.46 g, 56.0%yield) as a beige solid.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutyl-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps C-G in Example 1, and using6-isobutyl-2-methylpyridin-3-amine in place of 2-methyl-4-phenoxyanilinein step C, and using (R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one(Intermediate 15), PYOXIM, and diisopropylethylamine in place oftert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU, andtriethylamine in step G. Atropisomers were resolved by chiral SFC(Stationary phase: Chiralpak AS-H; 5 m, 250×20 mm, Mobile phase: 65%CO₂, 35% MeOH), to give the title compound. MS (ESI): mass calcd. forC₂₇H₃₀N₆O₃S, 518.6; m/z found, 519.1 [M+H]+. ¹H NMR (400 MHz, DMSO-d₆):δ 10.32 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.20-8.07 (m, 1H), 7.75 (d,J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.89-6.71 (m, 1H), 6.11 (d,J=16.8 Hz, 1H), 5.92 (d, J=5.4 Hz, 1H), 5.68 (d, J=10.5 Hz, 1H),4.55-4.17 (m, 1H), 4.10-3.95 (m, 1H), 3.85-3.73 (m, 1H), 3.18-2.93 (m,1H), 2.84-2.63 (m, 3H), 2.28 (s, 3H), 2.17-2.05 (m, 1H), 2.01-1.90 (m,1H), 1.85-1.73 (m, 1H), 1.71-1.58 (m, 1H), 1.52-1.34 (m, 1H), 0.94 (d,J=6.6 Hz, 6H).

Example 19:(E)-1-(2-Cyano-4,4-dimethylpent-2-enoyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide

The title compound was prepared using conditions analogous to Example877, and usingN-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide(Example 828) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889). MS (ESI): mass calcd. for C₃₅H₃₄N₆O₄S, 634.7; m/z found,635.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.45-11.12 (m, 1H), 10.67(br, 1H), 8.15 (d, J=5.5 Hz, 1H), 7.49-7.41 (m, 2H), 7.36 (dd, J=3.1,8.6 Hz, 1H), 7.23-7.18 (m, 1H), 7.15-7.10 (m, 2H), 7.10-7.07 (m, 1H),6.97 (dd, J=2.5, 8.5 Hz, 1H), 6.84 (s, 1H), 5.85 (d, J=5.5 Hz, 1H),4.44-3.76 (m, 2H), 3.24-3.12 (m, 1H), 3.10-2.94 (m, 1H) 2.83-2.66 (m,1H), 2.15-2.10 (m, 1H), 2.08 (s, 3H), 1.88-1.65 (m, 2H), 1.58-1.39 (m,1H), 1.23 (s, 9H).

Example 817:1-(2-Cyanoacetyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide

The title compound was prepared using analogous conditions in Example181, and usingN-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide(Example 828) in place of(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860). MS (ESI): mass calcd. for C₃₀H₂₆N₆O₄S, 566.6; m/z found,567.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.20-11.09 (m, 0.5H), 10.65(s, 0.5H), 10.52-10.48 (m, 0.5H), 10.44 (s, 0.5H), 8.15-8.10 (m, 1H),7.48-7.42 (m, 2H), 7.38-7.32 (m, 1H), 7.20 (t, J=7.4 Hz, 1H), 7.15-7.07(m, 3H), 6.97 (dd, J=2.8, 8.5 Hz, 1H), 5.84-5.80 (m, 1H), 4.50-4.42 (m,0.5H), 4.40-4.31 (m, 0.5H), 4.23-4.00 (m, 2H), 3.86-3.76 (m, 0.5H),3.69-3.58 (m, 0.5H), 3.26-3.15 (m, 0.5H), 3.09-2.98 (m, 0.5H), 2.91-2.64(m, 2H), 2.07 (s, 3H), 2.06-2.00 (m, 1H), 1.80-1.62 (m, 2H), 1.59-1.29(m, 1H).

Example 20:N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)-1-propionylpiperidine-3-carboxamide

The title compound was prepared using conditions analogous to Example75, and usingN-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide(Example 828) and propionic acid in place of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869). MS (ESI): mass calcd. for C₃₀H₂₉N₅O₄S, 555.6; m/z found,556.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.26-10.19 (m, 1H),10.18-10.09 (m, 1H), 8.16 (d, J=5.5 Hz, 1H), 7.49-7.41 (m, 2H),7.39-7.33 (m, 1H), 7.20 (t, J=7.3 Hz, 1H), 7.15-7.07 (m, 3H), 6.98 (dd,J=2.5, 8.5 Hz, 1H), 5.86 (d, J=5.5 Hz, 1H), 4.55-4.47 (m, 0.5H),4.27-4.19 (m, 0.5H), 4.02-3.94 (m, 0.5H), 3.84-3.77 (m, 0.5H), 3.28-3.17(m, 1H), 3.09-2.99 (m, 1H), 2.82-2.73 (m, 1H), 2.43-2.33 (m, 2H), 2.08(s, 3H), 2.03-1.97 (m, 1H), 1.79-1.65 (m, 2H), 1.44-1.33 (m, 1H), 1.01(t, J=7.4 Hz, 3H).

Example 21:1-(2-Cyanoacetyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide

The title compound was prepared using using conditions analogous toExample 181, and usingN-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide(Example 833). MS (ESI): mass calcd. for C₃₀H₂₆N₆O₄S, 566.6; m/z found,567.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.40 (s, 1H), 10.34 (s, 1H),8.15 (d, J=5.5 Hz, 1H), 7.48-7.42 (m, 2H), 7.36 (d, J=8.5 Hz, 1H),7.23-7.18 (m, 1H), 7.14-7.08 (m, 3H), 6.98 (dd, J=2.8, 8.8 Hz, 1H), 5.86(d, J=5.5 Hz, 1H), 4.37-4.29 (m, 1H), 4.16-3.99 (m, 2H), 3.76-3.68 (m,1H), 3.18-3.07 (m, 1H), 2.82-2.72 (m, 1H), 2.70-2.60 (m, 1H), 2.08 (s,3H), 1.96-1.85 (m, 2H), 1.76-1.61 (m, 1H), 1.59-1.44 (m, 1H).

Example 22:1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide

The title compound was prepared using conditions analogous to Example75, and usingN-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide(Example 833), acrylic acid, HATU, and diisopropylethylamine. MS (ESI):mass calcd. for C₃₀H₂₇N₅O₄S, 553.6; m/z found, 554.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 10.51 (s, 1H), 10.38 (s, 1H), 8.14 (d, J=5.5 Hz, 1H),7.48-7.42 (m, 2H), 7.35 (d, J=8.5 Hz, 1H), 7.23-7.18 (m, 1H), 7.15-7.07(m, 3H), 6.98 (dd, J=2.8, 8.8 Hz, 1H), 6.84 (dd, J=10.4, 16.7 Hz, 1H),6.11 (dd, J=2.5, 16.6 Hz, 1H), 5.85 (d, J=5.3 Hz, 1H), 5.68 (dd, J=2.5,10.6 Hz, 1H), 4.46-4.42 (m, 1H), 4.14-4.10 (m, 1H), 3.24-3.10 (m, 1H),2.82-2.72 (m, 1H), 2.71-2.63 (m, 1H), 2.07 (s, 3H), 1.97-1.88 (m, 2H),1.63-1.45 (m, 2H).

Example 23:1-Ethyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide

To a solution ofN-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide(Example 828) (100 mg, 0.187 mmol) in MeOH (6 mL) was added acetaldehyde(114 mg, 0.935 mmol) and was stirred for 30 min at 20° C. Next was addedsodium cyanoborohydride (59.0 mg, 0.935 mmol) and was stirred for h at20° C. The reaction was concentrated to dryness and the residue waspurified by preparative C18-reverse phase HPLC to give the titlecompound (45 mg, 99% yield). MS (ESI): mass calcd. for C₂₉H₂₉N₅O₃S,527.6; m/z found, 528.2 [M+H]⁺.

Example 24:1-Cyano-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide

The title compound was prepared using conditions analogs to Example 890,and usingN-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide(Example 833) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889). MS (ESI): mass calcd. for C₂₈H₂₄N₆O₃S, 524.6; m/z found,525.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.20 (s, 1H), 10.07 (s, 1H),8.14 (d, J=5.5 Hz, 1H), 7.48-7.42 (m, 2H), 7.35 (d, J=8.5 Hz, 1H),7.23-7.17 (m, 1H), 7.14-7.07 (m, 3H), 6.97 (dd, J=2.6, 8.7 Hz, 1H), 5.84(d, J=5.3 Hz, 1H), 3.49-3.42 (m, 2H), 3.18-3.09 (m, 2H), 2.07 (s, 3H),1.94-1.86 (m, 2H), 1.78-1.64 (m, 2H), 1.25-1.21 (m, 1H).

Example 25:1-Methyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide

To a solution ofN-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide(Example 828) (100 mg, 0.202 mmol) in MeOH (5.0 mL) was addedformaldehyde (84 mg, 1.0 mml, 37 wt. % in H₂O) and was stirred for 30minutes at 20° C. To the reaction was added sodium cyanoborohydride (64mg, 1.0 mmol) and was stirred for 1 h at 20° C. The reaction wasconcentrated to dryness and was extracted with ethyl acetate (20 mL).The organic layer was washed with water (20 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby preparative reverse phase C18 HPLC to give the title compound. MS(ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.2; m/z found, 514.2 [M+H]⁺. 1HNMR (400 MHz, DMSO-d₆): δ 11.58 (s, 1H), 10.70-10.67 (m, 1H), 10.62 (br,1H), 8.15 (d, J=5.5 Hz, 1H), 7.48-7.40 (m, 2H), 7.37-7.32 (m, 1H),7.23-7.18 (m, 1H), 7.15-7.06 (m, 3H), 6.97 (dd, J=2.7, 8.6 Hz, 1H), 5.84(d, J=5.4 Hz, 1H), 3.42-3.34 (m, 1.5H), 3.29-3.22 (m, 0.5H), 3.19-3.05(m, 2H), 2.97-2.85 (m, 1H), 2.84-2.73 (m, 3H), 2.22-2.13 (m, 1H), 2.08(s, 3H), 1.95-1.78 (m, 2H), 1.60-1.45 (m, 1H).

Example 824:5-(2-Methyl-4-phenoxyphenyl)-2-(4-methylpiperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

To a solution of5-(2-methyl-4-phenoxyphenyl)-2-(piperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one(Example 327, 100 mg, 0.202 mmol) in MeOH (5.0 mL) was addedformaldehyde (84 mg, 1.0 mml, 37 wt. % in H₂O) and was stirred for 30minutes at 20° C. To the reaction was added sodium cyanoborohydride (64mg, 1.0 mmol) and was stirred for 1 h at 20° C. The reaction wasconcentrated to dryness and was extracted with ethyl acetate (20 mL).The organic layer was washed with water (20 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated to dryness. The residue was purifiedby preparative reverse phase C18 HPLC to give the title compound (5.9mg, 5.6% yield). MS (ESI): mass calcd. for C₂₆H₂₅N₅O₂S, 471.6; m/zfound, 472.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.19 (d, J=5.5 Hz, 1H),7.46-7.40 (m, 3H) 7.28 (d, J=8.8 Hz, 1H), 7.22-7.17 (m, 1H), 7.11 (d,J=8.0 Hz, 1H), 7.08 (d, J=2.5 Hz, 1H), 7.00 (dd, J=2.8, 8.8 Hz, 1H),5.95 (d, J=5.5 Hz, 1H), 3.58-3.54 (m, 4H), 3.31-3.20 (m, 4H), 3.02 (s,3H), 2.15 (s, 3H).

Example 825:(E)-4,4-Dimethyl-2-(4-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperazine-1-carbonyl)pent-2-enenitrile

To a solution of5-(2-methyl-4-phenoxyphenyl)-2-(piperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one(Example 327, 100 mg, 0.202 mmol), (E)-2-cyano-4,4-dimethylpent-2-enoicacid (Intermediate 44) (37.1 mg, 0.242 mmol), and diisopropylethylamine(78.3 mg, 0.606 mmol) in DCM (5 mL) at 0° C. was added PyBrOP (141 mg,0.303 mmol) and was stirred for 1 h at 20° C. The residue was purifiedby preparative HPLC to give the title compound (30 mg, 20% yield). MS(ESI): mass calcd. for C₃₃H₃₂N₆O₃S, 592.7; m/z found, 593.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 10.68 (s, 1H), 8.14 (d, J=5.4 Hz, 1H),7.48-7.42 (m, 2H), 7.34 (d, J=8.6 Hz, 1H), 7.24-7.17 (m, 1H), 7.14-7.07(m, 3H), 6.97 (dd, J=2.7, 8.6 Hz, 1H), 6.91 (s, 1H), 5.83 (d, J=5.4 Hz,1H), 3.73-3.64 (m, 4H), 2.97-2.88 (m, 4H), 2.07 (s, 3H), 1.25 (s, 9H).

Example 826:4-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperazine-1-carbonitrile

To a solution of5-(2-methyl-4-phenoxyphenyl)-2-(piperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one(Example 327, 100 mg, 0.202 mmol) and cyanogen bromide (21.4 mg, 0.202mmol) in THF (2 mL) at 0° C. was added triethylamine (61.3 mg, 0.606mmol) and was stirred for 12 h at 20° C. The residue was purified bypreparative HPLC to give the title compound (30 mg, 24% yield). MS(ESI): mass calcd. for C₂₆H₂₂N₆O₂S, 482.6; m/z found, 483.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 10.65 (s, 1H), 8.15 (d, J=5.4 Hz, 1H),7.48-7.42 (m, 2H), 7.34 (d, J=8.6 Hz, 1H), 7.22-7.16 (m, 1H), 7.14-7.07(m, 3H), 6.97 (dd, J=2.8, 8.4 Hz, 1H), 5.83 (d, J=5.4 Hz, 1H), 3.47-3.40(m, 4H), 2.99-2.92 (m, 4H), 2.06 (s, 3H).

Example 827:5-(2-Methyl-4-phenoxyphenyl)-2-(4-propionylpiperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one

The title compound was prepared using analogous conditions as found inExample 75, and using5-(2-methyl-4-phenoxyphenyl)-2-(piperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one(Example 327) and propionic acid in place of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869). MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.6; m/z found,514.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 1H), 8.16 (d, J=5.5Hz, 1H), 7.49-7.42 (m, 2H), 7.35 (d, J=8.6 Hz, 1H), 7.23-7.18 (m, 1H),7.15-7.06 (m, 3H), 6.98 (dd, J=2.8, 8.6 Hz, 1H), 5.85 (d, J=5.5 Hz, 1H),3.68-3.55 (m, 4H), 2.91-2.78 (m, 4H), 2.37 (q, J=7.4 Hz, 2H), 2.07 (s,3H), 1.01 (t, J=7.4 Hz, 3H).

Example 828:N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, step G-H in Example 1, and using2-amino-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one(Intermediate 56), (±)1-Boc-piperidine-3-carboxylic acid, anddiisopropylethylamine in place of4-[2-methyl-N-(methylcarbamoyl)-4-phenoxyanilino]-3a,4-dihydrothieno[2,3-b]pyridine-2-carboxylicacid, tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, andtriethylamine in step G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S, 499.6;m/z found, 500.2 [M+H]⁺.

Example 829:(E)-1-(2-Cyano-4,4-dimethylpent-2-enoyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-358-triazaacenaphthylen-2-yl)piperidine-4-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, steps I in Example 1, and usingN-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide(Example 833), (E)-2-cyano-4,4-dimethylpent-2-enoic acid (Intermediate44), HATU, diisopropylethylamine, and DMF in place ofN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,prop-2-enoyl chloride, DCM, and triethylamine. MS (ESI): mass calcd. forC₃₅H₃₄N₆O₄S, 634.7; m/z found, 635.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 10.69 (br, 1H), 10.44 (br, 1H), 8.12 (d, J=5.4 Hz, 1H), 7.49-7.42 (m,2H), 7.35 (d, J=8.6 Hz, 1H), 7.20 (t, J=7.4 Hz, 1H), 7.12 (d, J=7.7 Hz,2H), 7.09 (d, J=2.6 Hz, 1H), 6.97 (dd, J=2.7, 8.6 Hz, 1H), 6.84 (s, 1H),5.82 (d, J=5.4 Hz, 1H), 4.36-4.20 (m, 1H), 3.96-3.80 (m, 1H), 3.30-3.19(m, 1H), 2.97-2.80 (m, 1H), 2.78-2.65 (m, 1H), 2.07 (s, 3H), 2.03-1.88(m, 2H), 1.74-1.55 (m, 2H), 1.24 (s, 9H).

Example 26:(E)-1-(2-Cano-3-cyclopropylacryloyl)-N-(5-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide

The title compound was prepared using conditions analogous to Example877, and, usingN-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide(Example 833). MS (ESI): mass calcd. for C₃₄H₃₀N₆O₄S, 618.7; m/z found,619.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.75-10.60 (m, 1H),10.46-10.40 (m, 1H), 8.13 (d, J=5.4 Hz, 1H), 7.48-7.42 (m, 2H), 7.35 (d,J=8.6 Hz, 1H), 7.23-7.17 (m, 1H), 7.14-7.10 (m, 2H), 7.09 (d, J=2.6 Hz,1H), 6.97 (dd, J=2.7, 8.6 Hz, 1H), 6.62 (d, J=11.1 Hz, 1H), 5.83 (d,J=5.4 Hz, 1H), 3.21-2.85 (m, 2H), 2.77-2.65 (m, 2H), 2.07 (s, 3H),2.00-1.85 (m, 3H), 1.70-1.55 (m, 2H), 1.26-1.20 (m, 1H), 1.20-1.15 (m,2H), 0.96-0.90 (m, 2H).

Example 831:1-Methyl-N-(5-(2-methyl-4-phenoxyphenl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide

To a solution ofN-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide(Example 833) (150 mg, 0.28 mmol) in MeOH (10 mL) was added formaldehyde(3.0 mL, 37 wt. % in H₂O) and was stirred for 30 minutes at 20° C. Nextwas added sodium cyanoborohydride (88 mg, 1.4 mmol) and was stirred for1 h at 20° C. The reaction was concentrated to dryness, extracted withEtOAc (20 mL), the organic phase was collected, washed with water (20mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness.The residue was purified by preparative C18-reverse phase HPLC to givethe title compound (25 mg, 16% yield). MS (ESI): mass calcd. forC₂₈H₂₇N₅O₃S, 513.6; m/z found, 514.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 10.94 (s, 1H), 10.15 (br, 1H), 8.21 (d, J=5.8 Hz, 1H), 7.49-7.42 (m,2H), 7.37 (d, J=8.6 Hz, 1H), 7.24-7.18 (m, 1H), 7.15-7.08 (m, 2H), 7.09(d, J=2.6 Hz, 1H), 6.98 (dd, J=2.8, 8.6 Hz, 1H), 5.92 (d, J=5.8 Hz, 1H),3.52-3.43 (m, 2H), 3.07-2.94 (m, 2H), 2.80-2.77 (m, 1H), 2.76-2.74 (m,3H), 2.16-2.10 (m, 2H), 2.08 (s, 3H), 1.99-1.86 (m, 2H).

Example 832:1-Ethyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide

To a solution ofN-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide(Example 833) (150 mg, 0.28 mmol) in MeOH (10 mL) was added acetaldehyde(3.0 mL) and was stirred for 30 minutes at 20° C. Next was added sodiumcyanoborohydride (88 mg, 1.4 mmol) and was stirred for 1 h at 20° C. Thereaction was concentrated to dryness, extracted with EtOAc (20 mL), theorganic phase was collected, washed with water (20 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue waspurified by preparative C18-reverse phase HPLC to give the titlecompound (45 mg, 29% yield). MS (ESI): mass calcd. for C₂₉H₂₉N₅O₃S,527.6; m/z found, 528.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.00 (s,1H), 10.08 (br, 1H), 8.22 (d, J=5.8 Hz, 1H), 7.51-7.41 (m, 2H), 7.37 (d,J=8.6 Hz, 1H), 7.24-7.17 (m, 1H), 7.15-7.11 (m, 2H), 7.09 (d, J=2.6 Hz,1H), 6.98 (dd, J=2.7, 8.5 Hz, 1H), 5.95-5.91 (m, 1H), 3.58-3.50 (m, 2H),3.16-3.04 (m, 2H), 3.00-2.88 (m, 2H), 2.87-2.76 (m, 1H), 2.20-2.10 (m,2H), 2.08 (s, 3H), 2.04-1.90 (m, 2H), 1.29-1.21 (m, 3H).

Example 833:N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide

The title compound was prepared using analogous conditions as found inMethod 1, step G-H in Example 1, and using2-amino-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one(Intermediate 56), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid,PyBOP, and diisopropylethylamine in place of4-[2-methyl-N-(methylcarbamoyl)-4-phenoxyanilino]-3a,4-dihydrothieno[2,3-b]pyridine-2-carboxylicacid, tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate, HATU,and triethylamine in step G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S,499.6; m/z found, 500.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 11.84 (br,1H), 10.85 (br, 1H), 8.25 (br, 1H), 8.09 (d, J=5.4 Hz, 1H), 7.48-7.42(m, 2H), 7.33 (d, J=8.6 Hz, 1H), 7.22-7.18 (m, 1H), 7.15-7.10 (m, 2H),7.08 (d, J=2.6 Hz, 1H), 6.96 (dd, J=8.5, 2.6 Hz, 1H), 5.78 (d, J=5.3 Hz,1H), 3.26-3.17 (m, 2H), 2.85-2.74 (m, 3H), 2.07 (s, 3H), 2.02-1.93 (m,2H), 1.87-1.72 (m, 2H).

Example 834:(R)-5-(*S)-(2-Methyl-4-phenoxyphenl)-4-oxo-N-(1-(vinylsulfonyl)pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral Resolution Method A after step F to obtain the *Satropisomer), and using (R)-tert-butyl 3-aminopyrrolidine-1-carboxylatein place of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, and using ethenesulfonyl chloride in placeof prop-2-enoyl chloride in step I. MS (ESI): mass calcd. forC₂₈H₂₅N₅O₅S₂, 575.7; m/z found, 576.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.33 (d, J=5.6 Hz, 1H), 7.47-7.35 (m, 2H), 7.29 (d, J=8.6 Hz, 1H),7.20-7.13 (m, 1H), 7.12-7.03 (m, 3H), 6.99-6.93 (m, 1H), 6.77-6.65 (m,1H), 6.20 (d, J=16.5 Hz, 1H), 6.12-6.03 (m, 2H), 4.57-4.48 (m, 1H),3.65-3.56 (m, 1H), 3.54-3.44 (m, 1H), 3.39-3.32 (m, 1H), 3.29-3.22 (m,1H), 2.33-2.22 (m, 1H), 2.11 (s, 3H), 2.09-2.00 (m, 1H).

Example 835:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-Methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamidehydrochloride

To a solution of tert-butyl (R)-3-aminopiperidine-1-carboxylate (296 mg,1.48 mmol) in THF was added 1N AlMe₃ solution (3 mL, 3 mmol), thenstirred at room temperature for 1 hour. A solution of methyl5-(2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(Intermediate 73) (260 mg, 0.49 mmol) in THF was added and heated atreflux for 16 hours. The mixture was filtered, washed with DCM and MeOH.The filtrate was concentrated and purified by flash columnchromatography eluting with DCM/MeOH to give a yellow solid, which wasdissolved in MeOH and 5N HCl aq solution. The solution was concentratedat 50° C. under vacuo to yield the title compound as a yellow solid.

Step B:(R,E)-N-(1-(2-cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to in Example877 and using(R)-5-(2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamidehydrochloride in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) to give a yellow solid.

Example 836:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-fluoro-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phen)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using steps A-B in Example 835, usingmethyl5-(2-fluoro-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(Intermediate 74) in place of methyl5-(2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(Intermediate 73) in step A as a yellow solid.

Example 837:(R)—N-(1-Cyanopyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example890, and using(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 159) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) to give a yellow solid. MS (ESI): mass calcd. forC₂₇H₂₂N₆O₃S, 510.6; m/z found, 511.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 10.21 (s, 1H), 8.38-8.26 (m, 2H), 7.53-7.27 (m, 3H), 7.24-6.86 (m,5H), 5.96 (d, J=5.3 Hz, 1H), 4.45 (d, J=5.4 Hz, 1H), 3.64-3.31 (m, 4H),2.21-1.87 (m, 5H).

Example 838:(R)—N-(1-(2-Cyanoacetyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example181, and using(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 159) in place of(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860) to give a yellow solid. MS (ESI): mass calcd. forC₂₉H₂₄N₆O₄S, 552.6; m/z found, 553.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 10.20 (s, 1H), 8.42-8.28 (m, 2H), 7.50-7.41 (m, 2H), 7.38 (d, J=8.6Hz, 1H), 7.24-7.18 (m, 1H), 7.16-7.06 (m, 3H), 7.04-6.93 (m, 1H),6.03-5.94 (m, 1H), 4.59-4.35 (m, 1H), 3.98-3.90 (m, 2H), 3.79-3.62 (m,1H), 3.58-3.35 (m, 3H), 2.25-1.95 (m, 5H).

Example 839:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I, and using (R)-tert-butyl 3-aminopiperidine-1-carboxylate in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₃₀H₂₇N₅O₄S,553.6; m/z found, 554.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.29-10.20(m, 1H), 8.37-8.32 (m, 1H), 8.13-8.04 (m, 1H), 7.50-7.35 (m, 3H),7.25-7.17 (m, 1H), 7.17-7.07 (m, 3H), 7.02-6.95 (m, 1H), 6.87-6.73 (m,1H), 6.16-6.06 (m, 1H), 6.03-5.97 (m, 1H), 5.72-5.64 (m, 1H), 4.54-4.18(m, 1H), 4.10-3.95 (m, 1H), 3.84-3.74 (m, 1H), 3.17-2.92 (m, 1H),2.82-2.62 (m, 1H), 2.07 (s, 3H), 2.00-1.88 (m, 1H), 1.84-1.74 (m, 1H),1.74-1.61 (m, 1H), 1.51-1.36 (m, 1H).

Example 840:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example877, and using(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 466) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889). MS (ESI): mass calcd. for C₃₃H₂₈N₆O₄S, 604.7; m/z found,605.3[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.28 (d, J=5.6 Hz, 1H),7.58-7.52 (m, 1H), 7.40-7.30 (m, 2H), 7.18-7.09 (m, 3H), 7.09-7.03 (m,3H), 6.52 (d, J=11.0 Hz, 1H), 6.16 (d, J=5.6 Hz, 1H), 4.26-4.10 (m, 1H),4.08-3.92 (m, 2H), 3.25-2.95 (m, 2H), 2.09-1.93 (m, 2H), 1.90-1.82 (m,1H), 1.78-1.57 (m, 2H), 1.23-1.15 (m, 2H), 1.01-0.92 (m, 1H), 0.87-0.78(m, 1H).

Example 841:(R)—N-(1-(3-Methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example75, and using 3-methoxypropanoic acid in place of 3-hydroxypropanoicacid. MS (ESI): mass calcd. for C₃₁H₃₁N₅O₅S, 585.9; m/z found,586.7[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.32-8.27 (m, 1H), 7.42-7.34 (m,2H), 7.33-7.28 (m, 1H), 7.18-7.11 (m, 1H), 7.09-7.02 (m, 3H), 6.99-6.93(m, 1H), 6.07-6.01 (m, 1H), 4.50-4.24 (m, 1H), 4.13-3.84 (m, 2H),3.68-3.61 (m, 2H), 3.30 (s, 3H), 3.19-2.98 (m, 1H), 2.87-2.76 (m, 1H),2.73-2.62 (m, 2H), 2.11 (s, 3H), 2.07-1.98 (m, 1H), 1.87-1.77 (m, 1H),1.73-1.47 (m, 2H).

Example 842:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′,3′-difluoro-4-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: tert-butyl(R)-3-(5-(5-bromo-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

The title compound was prepared in a manner analogous to Method 1, stepsB-G in Example 1, using 5-bromo-2-methylaniline in place of2-Methyl-4-phenoxyaniline in step B, using tert-butyl(R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G as a yellow solid.

Step B: (R)-5-(2′,3′-difluoro-4-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The mixture of tert-butyl(R)-3-(5-(5-bromo-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate,2-(2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,Pd(dppf)Cl₂, and Cs₂CO₃ in p-dioxane was stirred at 80° C. under N₂ for4 hours, then was directly purified by ISCO eluting with MeOH/water. Theproduct was dissolved in saturated aqueous HCl and MeOH, stirred at roomtemperature for 30 minutes, the solvent was removed under vacuo. Theresidue was purified by preparative TLC eluting with MeOH/DCM to yieldthe title compound as a brown solid.

Step C:(R)—N-(1-acryloylpiperidin-3-yl)-5-(2′,3′-difluoro-4-methyl-[11′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, using (R)-5-(2′,3′-difluoro-4-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamidein place ofN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.MS (ESI): mass calcd. for C₃₀H₂₅F₂N₅O₃S, 573.6; m/z found, 574.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ 8.32 (d, J=4.7 Hz, 1H), 7.71-7.63 (m, 1H),7.62-7.54 (m, 2H), 7.35-7.17 (m, 3H), 6.85-6.72 (m, 1H), 6.26-6.14 (m,1H), 6.08 (d, J=4.7 Hz, 1H), 5.78-5.67 (m, 1H), 4.61-4.46 (m, 1H),4.33-4.13 (m, 1H), 3.99-3.92 (m, 1H), 3.22-3.15 (m, 1H), 3.00-2.81 (m,1H), 2.23 (s, 3H), 2.11-2.02 (m, 1H), 1.94-1.81 (m, 1H), 1.82-1.65 (m,1H), 1.64-1.53 (m, 1H).

Example 843:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example104, and using propionic acid in place of 3-methylsulfonylpropanoic acidto give a yellow solid. MS (ESI): mass calcd. for C₂₉H₂₇N₅O₄S, 541.6;m/z found, 542.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.24 (s, 1H),8.45-8.21 (m, 2H), 7.57-7.32 (m, 3H), 7.29-6.84 (m, 5H), 6.04-5.94 (m,1H), 4.62-4.29 (m, 1H), 3.79-3.35 (m, 3H), 2.29-1.91 (m, 7H), 0.99 (t,J=6.4 Hz, 3H).

Example 844:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)pyrrolidin-3-yl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example877, and using(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 159) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) to give a white solid. MS (ESI): mass calcd. forC₃₃H₂₈N₆O₄S, 604.7; m/z found, 605.1 [M+H]⁺. ¹H NMR (400 MHz, a mixtureof CD₃OD and DMSO-d₆): δ 8.29 (d, J=5.4 Hz, 1H), 7.44-7.35 (m, 2H),7.34-7.25 (m, 1H), 7.18-7.11 (m, 1H), 7.10-7.01 (m, 3H), 6.98-6.89 (m,1H), 6.76-6.70 (m, 1H), 5.97 (d, J=5.5 Hz, 1H), 4.54-4.45 (m, 1H),3.79-3.71 (s, 3H), 3.64-3.55 (m, 1H), 3.50-3.43 (m, 1H), 2.22-2.11 (m,1H), 2.05 (s, 3H), 1.97-1.89 (m, 1H), 1.21-1.15 (m, 2H), 0.95-0.84 (m,2H).

Example 845:(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(4-(pyrrolidin-1-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I (including Chiral Resolution Method A after step F to obtain the *Satropisomer) in Example 1, and using tert-butyl(3R)-3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, and using (E)-4-(pyrrolidin-1-yl)but-2-enoic acid, HATU, DIPEA,and DMF in place of prop-2-enoyl chloride, trimethylamine, and DCM instep I. MS (ESI): mass calcd. for C₃₅H₃₆N₆O₄S, 636.8; m/z found, 637.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.37-8.31 (m, 1H), 7.42-7.33 (m, 2H),7.21-7.12 (m, 2H), 7.12-7.06 (m, 2H), 7.01-6.98 (m, 1H), 6.98-6.84 (m,2H), 6.49-6.41 (m, 1H), 6.25 (br, 1H), 6.03-5.95 (m, 1H), 5.50 (br, 1H),4.15-3.34 (m, 5H), 3.32-3.18 (m, 2H), 2.64-2.40 (m, 4H), 2.12 (s, 3H),2.08-1.86 (m, 2H), 1.83-1.71 (m, 6H).

Example 846:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: Methyl3-amino-4-((4-(pyridin-2-yloxy)phenyl)amino)thieno[2,3-b]pyridine-2-carboxylate

To a solution of 4-(pyridin-2-yloxy)aniline 3.00 g, 16.1 mmol) and2-chloro-4-iodopyridine-3-carbonitrile (5.539 g, 20.94 mmol) in dioxane(30 mL) were added DPEphos (1.735 g, 3.221 mmol), Pd(OAc)₂ (0.362 g,1.61 mmol), and Cs₂CO₃ (10.498 g, 32.222 mmol) under a N₂ atmosphere andwas stirred at 100° C. for 4 h. After 4 h, methyl 2-mercaptoacetate(2.565 g, 24.17 mmol) was added and the reaction was stirred at 100° C.overnight. The reaction was filtered to remove the solid and wasconcentrated to dryness. MeOH was added to the residue with stirring andthe precipitate that formed was filtered. The precipitate was added toEtOAc, stirred, filtered, and dried under a vacuum to give the titlecompound (2.7 g, 43% yield) as a grey solid.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsE-G in Example 1, and using methyl3-amino-4-((4-(pyridin-2-yloxy)phenyl)amino)thieno[2,3-b]pyridine-2-carboxylatein place of methyl3-amino-4-(2-methyl-4-phenoxyanilino)thieno[2,3-b]pyridine-2-carboxylatein step E, and using (R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one(Intermediate 15) in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₄S, 540.6; m/z found, 541.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.24 (br, 1H), 8.39-8.27 (m, 1H),8.26-8.12 (m, 2H), 7.98-7.84 (m, 1H), 7.52-7.42 (m, 2H), 7.38-7.29 (m,2H), 7.23-7.16 (m, 1H), 7.17-7.09 (m, 1H), 6.89-6.70 (m, 1H), 6.16-6.07(m, 1H), 6.06-5.98 (m, 1H), 5.74-5.61 (m, 1H), 4.57-3.87 (m, 2H),3.86-3.68 (m, 1H), 3.18-2.96 (m, 1H), 2.88-2.61 (m, 1H), 2.03-1.89 (m,1H), 1.83-1.73 (m, 1H), 1.72-1.58 (m, 1H), 1.50-1.37 (m, 1H).

Example 847:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsG-I, in Example 1, using5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 75) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27), and using tert-butyl(R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₇H₃₀N₆O₅S, 670.7; m/z found, 671.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.77 (br, 1H), 8.17-8.07 (m, 1H),7.75-7.68 (m, 1H), 7.66-7.60 (m, 1H), 7.48-7.41 (m, 1H), 7.34-7.14 (m,4H), 7.10-7.01 (m, 3H), 6.96-6.90 (m, 1H), 6.62-6.49 (m, 1H), 6.15-6.06(m, 1H), 5.80-5.67 (m, 1H), 5.67-5.58 (m, 1H), 5.30 (s, 2H), 4.52-4.34(m, 1H), 3.89-3.60 (m, 2H), 3.60-3.47 (m, 1H), 3.45-3.40 (m, 1H),2.21-2.08 (m, 1H), 1.99 (s, 3H), 1.96-1.86 (m, 1H).

Example 848:5-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((R)-2-(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example75, and using (R)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acidin place of 3-hydroxypropanoic acid to give tert-butylmethyl((R)-1-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-1-oxopropan-2-yl)carbamate.This product was then subjected to conditions analogous to those inMethod 1, step H, to give the title compound. MS (ESI): mass calcd. forC₃₁H₃₂N₆O₄S, 584.7; m/z found, 585.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.27-8.13 (m, 1H), 7.43-7.34 (m, 2H), 7.29-7.19 (m, 1H), 7.18-7.11 (m,1H), 7.10-7.01 (m, 3H), 7.00-6.91 (m, 1H), 6.00-5.86 (m, 1H), 4.44-3.43(m, 5H), 3.15-2.75 (m, 1H), 2.50-2.35 (m, 3H), 2.14-1.71 (m, 6H),1.70-1.52 (m, 1H), 1.34-1.23 (m, 3H).

Example 849:N—((R)-1-((R)-Azetidine-2-carbonyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example75, and using (R)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid inplace of 3-hydroxypropanoic acid to give (R)-tert-butyl2-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carbonyl)azetidine-1-carboxylate.This product was then subjected to conditions analogous to those inMethod 1, step H, to give the title compound. MS (ESI): mass calcd. forC₃₁H₃₀N₆O₄S, 582.7; m/z found, 583.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.07 (d, J=5.7 Hz, 1H), 7.45-7.31 (m, 2H), 7.23-7.04 (m, 4H), 7.04-7.00(m, 1H), 6.98-6.90 (m, 1H), 5.80 (d, J=5.7 Hz, 1H), 4.66-4.56 (m, 1H),4.29-3.88 (m, 2H), 3.77-3.64 (m, 1H), 3.54-3.38 (m, 2H), 3.20-3.02 (m,2H), 2.81-2.63 (m, 1H), 2.44-2.32 (m, 1H), 2.17-2.02 (m, 4H), 1.95-1.74(m, 2H), 1.66-1.54 (m, 1H).

Example 850:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example877, and using(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) to give a light yellow solid. MS (ESI): mass calcd. forC₃₄H₃₀N₆O₄S, 618.7; m/z found, 619.3 [M+H]⁺. ¹H NMR (400 MHz, a mixtureof CD₃OD and DMSO-d₆): δ 8.30-8.26 (m, 1H), 7.39-7.33 (m, 2H), 7.29-7.24(m, 1H), 7.15-7.09 (m, 1H), 7.08-7.00 (m, 3H), 6.94-6.89 (m, 1H),6.49-6.43 (m, 1H), 6.00-5.96 (m, 1H), 4.14-4.10 (m, 1H), 3.96-3.83 (m,2H), 3.11-2.92 (m, 2H), 2.05 (s, 3H), 1.98-1.86 (m, 2H), 1.82-1.75 (m,1H), 1.72-1.62 (m, 1H), 1.57-1.46 (m, 1H), 1.16-1.08 (m, 2H), 0.95-0.87(m, 1H), 0.82-0.73 (m, 1H).

Example 851:(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:4-Oxo-5-(3-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG-H in Example 1, and using4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 59) in place of5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid in step G.

Step B:(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example877, and using4-oxo-5-(3-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamidein place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) to give a yellow solid. MS (ESI): mass calcd. forC₃₃H₂₈N₆O₄S, 604.7; m/z found, 605.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.35 (d, J=5.6 Hz, 1H), 7.67-7.57 (m, 1H), 7.47-7.37 (m, 2H), 7.24-7.16(m, 3H), 7.15-7.10 (m, 3H), 6.58 (d, J=11.0 Hz, 1H), 6.23 (d, J=5.6 Hz,1H), 4.30-4.15 (m, 1H), 4.12-3.97 (m, 2H), 3.30-3.08 (m, 2H), 2.13-2.01(m, 2H), 1.98-1.89 (m, 1H), 1.85-1.74 (m, 1H), 1.72-1.61 (m, 1H),1.30-1.21 (m, 2H), 1.06-0.98 (m, 1H), 0.96-0.87 (m, 1H).

Example 852:(R)—N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example890, and using(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889). MS (ESI): mass calcd. for C₂₈H₂₄N₆O₃S, 524.6; m/z found,525.3[M+H]+. ¹H NMR (400 MHz, a mixture of DMSO-d₆ and CD₃OD): δ8.34-8.30 (m, 1H), 7.44-7.37 (m, 2H), 7.35-7.30 (m, 1H), 7.20-7.13 (m,1H), 7.12-7.03 (m, 3H), 6.99-6.92 (m, 1H), 6.01-5.96 (m, 1H), 4.02-3.94(m, 1H), 3.47-3.40 (m, 1H), 3.33-3.24 (m, 1H), 3.01-2.91 (m, 2H), 2.06(s, 3H), 1.95-1.84 (m, 1H), 1.83-1.74 (m, 1H), 1.70-1.50 (m, 2H).

Example 853:5-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((S)-2-(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, and using (S)-2-((tert-butoxycarbonyl)(methyl)amino)propanoicacid, HATU, DMF, and DIPEA in place of prop-2-enoyl chloride,triethylamine, and DCM in step I, followed by a Boc-deprotection stepusing concentrated HCl (3 mL) in MeOH (3 mL) and stirring for 30 min.The solvent was removed under a vacuum and the residue was purified byflash column chromatography to yield the title compound as a yellowsolid. MS (ESI): mass calcd. for C₃₁H₃₂N₆O₄S, 584.7; m/z found, 585.2[M+H]+. ¹H NMR (400 MHz, CD₃OD): δ 8.36-8.30 (m, 1H), 7.45-7.36 (m, 2H),7.32-7.25 (m, 1H), 7.21-7.14 (m, 1H), 7.12-7.04 (m, 3H), 7.01-6.94 (m,1H), 6.10-6.04 (m, 1H), 4.53-4.28 (m, 2H), 4.04-3.72 (m, 2H), 3.22-3.05(m, 1H), 2.96-2.83 (m, 1H), 2.70-2.56 (m, 3H), 2.14-2.09 (m, 3H),2.09-1.99 (m, 1H), 1.94-1.70 (m, 2H), 1.69-1.45 (m, 4H).

Example 854:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example866, steps A-B, and using tert-butyl (R)-3-aminopiperidine-1-carboxylatein place of tert-butyl-3-aminopiperidine-1-carboxylate in step A to givea white solid. MS (ESI): mass calcd. for C₂₈H₂₆N₆O₃S, 526.6; m/z found,527.1 [M+H]+. ¹H NMR (400 MHz, DMSO-d₆): δ 10.18 (s, 1H), 8.33 (d, J=5.4Hz, 1H), 8.14-8.05 (m, 1H), 7.52-7.45 (m, 2H), 7.44-7.37 (m, 2H),6.65-6.56 (m, 1H), 5.87 (d, J=5.4 Hz, 1H), 4.28-4.02 (m, 1H), 4.00-3.82(m, 2H), 3.12-2.78 (m, 2H), 2.11 (s, 3H), 2.02-1.92 (m, 1H), 1.92-1.86(m, 1H), 1.84-1.79 (m, 1H), 1.75-1.63 (m, 1H), 1.58-1.46 (m, 1H),1.20-1.13 (m, 2H), 1.07-0.95 (m, 1H), 0.91-0.84 (m, 1H).

Example 855:5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-N-(1-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example835, step A, and using methyl5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(Intermediate 76) (187 mg, 0.33 mmol) and 1-methylpiperidin-4-amine (76mg, 0.67 mmol) in place of methyl5-(2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate(Intermediate 73) and tert-butyl (R)-3-aminopiperidine-1-carboxylate togive a solid (88 mg, 41% yield). MS (ESI): mass calcd. for C₃₆H₃₂N₆O₄S,644.8; m/z found, 645.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.57-8.26(m, 1H), 8.19-8.08 (m, 1H), 7.74-7.70 (m, 1H), 7.67-7.62 (m, 1H),7.49-7.44 (m, 1H), 7.33-7.26 (m, 2H), 7.25-7.20 (m, 2H), 7.11-7.04 (m,3H), 6.97-6.92 (m, 1H), 5.82-5.71 (m, 1H), 5.32 (s, 2H), 3.75-3.68 (m,1H), 2.78-2.72 (m, 2H), 2.17 (s, 3H), 2.04-1.98 (m, 5H), 1.82-1.76 (m,2H), 1.59-1.51 (m, 2H).

Example 856:(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example877, and using5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 870) in place5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889). MS (ESI): mass calcd. for C₃₅H₃₂N₆O₅S, 648.7; m/z found,649.1 [M+H]⁺. ¹H NMR (400 MHz, a mixture of CD₃OD and DMSO-d₆): δ 8.29(d, J=5.4 Hz, 1H), 7.24-7.17 (m, 2H), 7.16-7.11 (m, 1H), 7.10-7.05 (m,1H), 7.00-6.93 (m, 1H), 6.90-6.85 (m, 1H), 6.79-6.72 (m, 1H), 6.52-6.44(m, 1H), 5.94 (d, J=5.5 Hz, 1H), 3.91-3.86 (m, 1H), 3.81 (s, 4H), 3.75(s, 3H), 2.02 (s, 3H), 1.99-1.86 (m, 2H), 1.84-1.75 (m, 1H), 1.73-1.63(m, 1H), 1.55-1.47 (m, 1H), 1.16-1.08 (m, 2H), 0.97-0.89 (m, 1H),0.85-0.76 (m, 1H).

Example 857:5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG in Example 1, using5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 75) in place of4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 58). MS (ESI): mass calcd. for C₃₅H₃₀N₆O₄S, 630.7;m/z found, 631.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.72-8.50 (m, 1H),8.31-8.22 (m, 1H), 8.21-8.13 (m, 1H), 7.78-7.69 (m, 1H), 7.68-7.59 (m,1H), 7.54-7.42 (m, 1H), 7.37-7.19 (m, 4H), 7.15-7.03 (m, 3H), 7.00-6.92(m, 1H), 5.80 (d, J=5.4 Hz, 1H), 5.32 (s, 2H), 3.28-3.22 (m, 2H),3.01-2.89 (m, 2H), 2.02 (s, 3H), 2.00-1.91 (m, 2H), 1.79-1.56 (m, 2H).

Example 858:5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example920 and using5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) in place of4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 58). MS (ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.6;m/z found, 514.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.30-8.23 (m, 1H),8.20-8.12 (m, 2H), 7.47-7.38 (m, 2H), 7.34-7.28 (m, 1H), 7.22-7.14 (m,1H), 7.13-7.02 (m, 3H), 6.98-6.91 (m, 1H), 5.90 (d, J=5.5 Hz, 1H),3.79-3.74 (m, 1H), 2.91-2.84 (m, 2H), 2.25 (s, 3H), 2.19-2.09 (m, 2H),2.03 (s, 3H), 1.84-1.73 (m, 2H), 1.68-1.57 (m, 2H).

Example 859:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example877, and using(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) to give a white solid. MS (ESI): mass calcd. forC₃₄H₃₀N₆O₄S, 618.7; m/z found, 619.4[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.31 (d, J=5.6 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.37-7.25 (m, 2H),7.11-7.04 (m, 2H), 7.04-6.96 (m, 3H), 6.56-6.44 (m, 1H), 6.05 (d, J=5.5Hz, 1H), 4.25-4.06 (m, 1H), 4.05-3.92 (m, 2H), 3.25-3.00 (m, 2H), 2.11(s, 3H), 2.07-1.94 (m, 2H), 1.91-1.82 (m, 1H), 1.77-1.54 (m, 2H),1.22-1.13 (m, 2H), 0.98-0.90 (m, 1H), 0.85-0.77 (m, 1H).

Example 860:(R)-4-Oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 4-fluoronitrobenzene in place of5-fluoro-2-nitrotoluene in step A, and using Pt/C and THF in place ofFe, EtOH/H₂O, and NH₄Cl in step B, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₆H₂₃N₅O₃S, 485.6; m/z found, 486.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.58 (s, 1H), 9.52 (s, 1H), 9.34 (s,1H), 8.14 (d, J=5.5 Hz, 1H), 7.42-7.33 (m, 4H), 7.27 (dd, J=8.8, 2.7 Hz,1H), 7.21-7.04 (m, 5H), 5.96 (d, J=5.5 Hz, 1H), 4.41 (d, J=9.5 Hz, 1H),3.60 (d, J=11.0 Hz, 1H), 3.19 (s, 4H), 2.04-1.95 (m, 2H).

Example 861:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example877, and using(R)-5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 78) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.MS (ESI): mass calcd. for C₄₂H₃₅N₇O₅S, 749.9; m/z found, 750.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): δ 8.24-8.09 (br, 1H), 7.74-7.68 (m, 1H),7.67-7.60 (m, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.34-7.18 (m, 4H), 7.12-7.02(m, 3H), 6.98-6.91 (m, 1H), 6.62-6.53 (m, 1H), 5.88-5.73 (m, 1H), 5.30(s, 2H), 3.90-3.76 (m, 2H), 2.00 (s, 3H), 1.97-1.87 (m, 2H), 1.85-1.71(m, 2H), 1.71-1.35 (m, 3H), 1.14-1.07 (m, 2H), 1.01-0.90 (m, 1H),0.88-0.75 (m, 2H).

Example 862:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example878, steps A-B, using tert-butyl (R)-3-aminopiperidine-1-carboxylate inplace of tert-butyl 3-aminopiperidine-1-carboxylate in Step A. MS (ESI):mass calcd. for C₂₉H₂₈N₆O₄S, 556.6; m/z found, 557.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 10.28 (s, 1H), 8.30-8.26 (m, 1H), 8.13-8.03 (m, 1H),7.30-7.17 (m, 1H), 7.04-6.95 (m, 1H), 6.95-6.87 (m, 1H), 6.65-6.47 (m,1H), 5.88-5.84 (m, 1H), 4.39-4.07 (br, 1H), 3.87-3.65 (m, 5H), 3.07-2.76(m, 2H), 2.03 (s, 3H), 1.93-1.81 (m, 2H), 1.80-1.73 (m, 1H), 1.70-1.59(m, 1H), 1.52-1.40 (m, 1H), 1.16-1.08 (m, 2H), 1.04-0.92 (m, 1H),0.88-0.78 (m, 1H).

Example 863:(S)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Method 1,step I, and using(S)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 912) in place ofN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.MS (ESI): mass calcd. for C₃₀H₂₇N₅O₄S, 553.6; m/z found, 554.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): δ 8.92 (d, J=7.4 Hz, 1H), 7.97 (d, J=5.5 Hz,1H), 7.44-7.36 (m, 2H), 7.17-7.11 (m, 1H), 7.11-7.03 (m, 3H), 6.99 (d,J=2.4 Hz, 1H), 6.91-6.85 (m, 1H), 6.71 (br, 1H), 6.06-6.00 (m, 1H), 5.70(s, 1H), 5.64-5.58 (m, 1H), 5.55 (d, J=5.5 Hz, 1H), 4.34-4.17 (m, 1H),4.05-3.71 (m, 3H), 3.10-2.93 (m, 1H), 2.82-2.68 (m, 1H), 1.98 (s, 3H),1.80-1.71 (m, 1H), 1.66-1.56 (m, 1H), 1.49-1.38 (m, 1H).

Example 864:(S)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, using tert-butyl (S)-3-aminopyrrolidine-1-carboxylatein place of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₉H₂₅N₅O₄S,539.6; m/z found, 540.5[M+H]⁺. ¹H NMR (400 MHz, a mixture of DMSO-d₆ andCD₃OD): δ 8.32-8.24 (m, 1H), 7.42-7.35 (m, 2H), 7.35-7.30 (m, 1H),7.18-7.11 (m, 1H), 7.10-7.01 (m, 3H), 6.97-6.90 (m, 1H), 6.62-6.48 (m,1H), 6.21-6.11 (m, 1H), 6.00-5.94 (m, 1H), 5.70-5.61 (m, 1H), 4.58-4.44(m, 1H), 3.75-3.67 (m, 1H), 3.64-3.57 (m, 1H), 3.56-3.39 (m, 2H),2.26-2.08 (m, 1H), 2.05 (s, 3H), 2.03-1.95 (m, 1H).

Example 865:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl 4-aminopiperidine-1-carboxylatein place of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S,499.6; m/z found, 500.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.78-8.68(br, 1H), 8.32 (s, 1H), 8.12 (d, J=5.3 Hz, 1H), 7.46-7.37 (m, 2H),7.24-7.00 (m, 6H), 6.96-6.88 (m, 1H), 5.72 (d, J=5.5 Hz, 1H), 4.01-3.97(m, 1H), 3.26-3.21 (m, 2H), 2.99-2.87 (m, 2H), 2.01 (s, 3H), 1.99-1.92(m, 2H), 1.73-1.59 (m, 2H).

Example 866:(R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared as in Example 75 using(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 98) and (E)-2-Cyano-4,4-dimethyl-pent-2-enoic acid or(E)-2-cyano-4,4-dimethylpent-2-enoic acid (Intermediate 44) in place of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) and 3-hydroxypropanoic acid. MS (ESI): mass calcd. forC₃₅H₃₄N₆O₄S, 634.7; m/z found, 635.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.34-8.28 (m, 1H), 7.43-7.36 (m, 2H), 7.34-7.27 (m, 1H), 7.20-7.12 (m,1H), 7.10-7.02 (m, 3H), 7.00-6.94 (m, 1H), 6.84 (s, 1H), 6.08-6.03 (m,1H), 4.46-3.80 (m, 3H), 3.50-2.84 (m, 2H), 2.17-1.99 (m, 4H), 1.97-1.85(m, 1H), 1.82-1.71 (m, 1H), 1.71-1.57 (m, 1H), 1.26 (s, 9H).

Example 867:(R,E)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(4-(pyrrolidin-1-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) (500 mg, 1.00 mmol) and (E)-4-(pyrrolidin-1-yl)but-2-enoicacid (776 mg, 2.00 mmol) in anhydrous DMF (5.0 mL) were added HATU (760mg, 2.00 mmol) and DIPEA (390 mg, 3.00 mmol) and was stirred for 30 minat rt. The reaction was purified by flash column chromatography to givethe title compound (78 mg, 12%) as a yellow solid. MS (ESI): mass calcd.for C₃₅H₃₆N₆O₄S, 636.8; m/z found, 637.3 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ 8.38-8.29 (m, 1H), 7.43-7.34 (m, 2H), 7.21-7.12 (m, 2H),7.12-7.06 (m, 2H), 7.01-6.99 (m, 1H), 6.98-6.82 (m, 2H), 6.53-6.43 (m,1H), 6.03-5.95 (m, 1H), 4.15-3.33 (m, 5H), 3.33-3.25 (m, 2H), 2.70-2.47(m, 4H), 2.14-2.10 (m, 3H), 2.09-1.82 (m, 4H), 1.81-1.76 (m, 4H).

Example 868:(R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example104, and using (E)-2-cyano-4,4-dimethyl-pent-2-enoic acid (Intermediate44) in place of 3-methylsulfonylpropanoic acid to give a yellow solid.MS (ESI): mass calcd. for C₃₄H₃₂N₆O₄S, 620.7; m/z found, 621.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.31-10.21 (m, 1H), 8.41-8.31 (m, 2H),7.49-7.42 (m, 2H), 7.39 (d, J=8.6 Hz, 1H), 7.24-7.18 (m, 1H), 7.16-7.08(m, 3H), 7.04-6.96 (m, 2H), 6.00 (d, J=5.5 Hz, 1H), 4.60-4.41 (m, 1H),3.90-3.42 (m, 4H), 2.25-2.14 (m, 1H), 2.10-1.98 (m, 4H), 1.27-1.21 (m,9H).

Example 27:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using tert-butyl(R)-3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S, 499.2; m/z found, 500.0[M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.07 (d, J=5.2 Hz,1H), 7.42-7.38 (m, 2H), 7.16-7.13 (m, 2H), 7.11-7.06 (m, 3H), 7.01-6.99(m, 1H), 6.93-6.88 (m, 1H), 5.70-5.64 (m, 1H), 3.95-3.87 (br, 1H),3.16-3.10 (m, 1H), 2.91-2.87 (m, 2H), 2.64-2.53 (m, 2H), 1.99 (s, 3H),1.91-1.88 (m, 1H), 1.76-1.70 (m, 1H), 1.55-1.45 (m, 2H).

Example 870:5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG-H, in Example 1, using5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 67) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27), using tert-butyl 3-aminopiperidine-1-carboxylatein place of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylateto yield the title product as a yellow solid. MS (ESI): mass calcd. forC₂₈H₂₇N₅O₄S, 529.6; m/z found, 530.1 [M+H]⁺. ¹H NMR (400 MHz, a mixtureof CD₃OD and DMSO-d₆): δ 8.23-8.10 (m, 1H), 7.21-7.16 (m, 1H), 7.15-7.09(m, 2H), 7.09-7.04 (m, 1H), 6.99-6.92 (m, 1H), 6.90-6.82 (m, 1H),6.78-6.66 (m, 1H), 5.84-5.74 (m, 1H), 4.05-4.01 (m, 1H), 3.76 (s, 3H),3.20-3.17 (m, 1H), 3.02-2.94 (m, 1H), 2.75-2.63 (m, 2H), 2.00 (s, 3H),1.96-1.88 (m, 1H), 1.84-1.76 (m, 1H), 1.66-1.54 (m, 2H).

Example 871:(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example75, and using propionic acid in place of 3-hydroxypropanoic acid to givea yellow solid. MS (ESI): mass calcd. for C₃₀H₂₉N₅O₄S, 555.7; m/z found,556.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.90 (s, 1H), 7.97 (d, J=5.1Hz, 1H), 7.43-7.35 (m, 2H), 7.17-7.11 (m, 1H), 7.11-7.03 (m, 3H), 6.99(s, 1H), 6.88 (d, J=6.9 Hz, 1H), 5.70 (s, 1H), 5.55 (d, J=5.1 Hz, 1H),4.21-3.97 (m, 1H), 3.92-3.58 (m, 2H), 3.08-2.97 (m, 1H), 2.77-2.69 (m,1H), 2.32-2.27 (m, 2H), 1.97 (s, 3H), 1.78-1.55 (m, 2H), 1.50-1.32 (m,2H), 1.01-0.91 (m, 3H).

Example 872:N-(1-Cyanopiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example890, and using5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 865) in place of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889). MS (ESI): mass calcd. for C₂₈H₂₄N₆O₃S, 524.6; m/z found,525.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.15 (s, 1H), 8.35-8.31 (m,1H), 8.06-8.01 (m, 1H), 7.46-7.39 (m, 2H), 7.38-7.34 (m, 1H), 7.21-7.15(m, 1H), 7.13-7.06 (m, 3H), 6.99-6.94 (m, 1H), 5.99-5.95 (m, 1H),3.97-3.90 (m, 1H), 3.44-3.36 (m, 2H), 3.17-3.10 (m, 2H), 2.05 (s, 3H),1.86-1.78 (m, 2H), 1.74-1.66 (m, 2H).

Example 873:(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example930, and using(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) in place of(S)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 912) to give a yellow solid. MS (ESI): mass calcd. forC₂₈H₂₇N₅O₃S, 513.6; m/z found, 514.4 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 8.74 (d, J=7.0 Hz, 1H), 7.98 (d, J=5.5 Hz, 1H), 7.45-7.35 (m, 2H),7.17-7.11 (m, 1H), 7.10-7.03 (m, 3H), 7.02-6.97 (m, 1H), 6.91-6.85 (m,1H), 5.55 (d, J=5.5 Hz, 1H), 3.94-3.83 (m, 1H), 2.77-2.72 (m, 1H),2.54-2.50 (m, 1H), 2.13 (s, 3H), 1.98 (s, 3H), 1.88-1.80 (m, 2H),1.71-1.62 (m, 1H), 1.54-1.46 (m, 1H), 1.27-1.17 (m, 2H).

Example 28:(R)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example181, and using(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) in place of(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860). MS (ESI): mass calcd. for C₃₀H₂₆N₆O₄S, 566.2; m/z found,567.2 [M+H]⁺. 1H NMR (400 MHz, DMSO-d6): δ 9.16-9.09 (m, 1H), 8.97-8.91(m, 1H), 7.98 (d, J=5.5 Hz, 1H), 7.44-7.36 (m, 2H), 7.16-7.12 (m, 1H),7.12-7.04 (m, 3H), 6.99 (d, J=2.4 Hz, 1H), 6.91-6.85 (m, 1H), 5.56 (d,J=5.5 Hz, 1H), 4.29-4.13 (m, 1H), 4.11-4.00 (m, 1H), 3.97-3.59 (m, 3H),3.14 (s, 2H), 1.98 (s, 3H), 1.86-1.82 (m, 1H), 1.70-1.63 (m, 1H),1.53-1.50 (m, 1H), 1.45-1.39 (m, 1H).

Example 875:(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:5-(2-Methyl-5-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG in Example 1, and using5-(2-methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 64) in place of5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27).

Step B:5-(2-Methyl-5-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions to Example877, and using5-(2-methyl-5-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamidein place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889). MS (ESI): mass calcd. for C₃₄H₃₀N₆O₄S, 618.7; m/z found,619.3[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.30 (d, J=5.5 Hz, 1H), 7.42 (d,J=8.5 Hz, 1H), 7.36-7.27 (m, 2H), 7.13-7.04 (m, 2H), 7.04-7.97 (m, 3H),6.58-6.46 (m, 1H), 6.04 (d, J=5.5 Hz, 1H), 4.26-4.08 (m, 1H), 4.06-3.92(m, 2H), 3.25-2.99 (m, 2H), 2.11 (s, 3H), 2.08-1.95 (m, 2H), 1.91-1.83(m, 1H), 1.79-1.69 (m, 1H), 1.66-1.56 (m, 1H), 1.24-1.13 (m, 2H),0.99-0.91 (m, 1H), 0.88-0.78 (m, 1H).

Example 876:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((R)-pyrrolidine-2

carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide.

The title compound was prepared using conditions analogous to Example75, and using (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acidin place of 3-hydroxypropanoic acid to give (R)-tert-butyl2-((R)-3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carbonyl)pyrrolidine-1-carboxylate.This product was then subjected to conditions analogous to those inMethod 1, step H, to give the title compound. MS (ESI): mass calcd. forC₃₂H₃₂N₆O₄S, 596.7; m/z found, 597.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.37-8.28 (m, 1H), 7.45-7.36 (m, 2H), 7.33-7.27 (m, 1H), 7.21-7.13 (m,1H), 7.12-7.04 (m, 3H), 7.02-6.93 (m, 1H), 6.11-6.03 (m, 1H), 4.69-4.35(m, 2H), 4.04-3.71 (m, 2H), 3.49-3.33 (m, 2H), 3.26-3.02 (m, 1H),2.99-2.75 (m, 1H), 2.59-2.37 (m, 1H), 2.15-1.59 (m, 10H).

Example 877:(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to 75, andusing5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) and (E)-2-cyano-3-cyclopropylprop-2-enoic acid(Intermediate 17) in place of(R)-4-Oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860). MS (ESI): mass calcd. for C₃₄H₃₀N₆O₄S, 618.7; m/z found,619.2 [M+H]⁺. ¹H NMR (400 MHz, a mixture of CD₃OD and DMSO-d₆): δ 8.32(d, J=5.5 Hz, 1H), 7.43-7.35 (m, 2H), 7.34-7.28 (m, 1H), 7.19-7.12 (m,1H), 7.10-7.02 (m, 3H), 6.97-6.92 (m, 1H), 6.54-6.46 (m, 1H), 6.00 (d,J=5.5 Hz, 1H), 4.00-3.94 (m, 1H), 3.91-3.83 (m, 2H), 3.06-2.94 (m, 2H),2.06 (s, 3H), 1.96-1.88 (m, 2H), 1.84-1.76 (m, 1H), 1.72-1.64 (m, 1H),1.55-1.45 (m, 1H), 1.17-1.09 (m, 2H), 1.01-0.90 (m, 1H), 0.85-0.77 (m,1H).

Example 878:(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:5-(4-Methoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 66)

The title compound was prepared in a manner analogous to Method 1, stepG in Example 1, and using5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 55) and tert-butyl-3-aminopiperidine-1-carboxylate inplace of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate.

Step B:(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example877, and using5-(4-methoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 66) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) to give a white solid. MS (ESI): mass calcd. forC₂₉H₂₈N₆O₄S, 556.6; m/z found, 557.1 [M+H]⁺. ¹H NMR (400 MHz, a mixtureof CD₃OD and DMSO-d₆): δ 8.25 (d, J=5.2 Hz, 1H), 7.21-7.14 (m, 1H),6.98-6.91 (m, 1H), 6.91-6.84 (m, 1H), 6.50-6.40 (m, 1H), 5.91 (d, J=5.4Hz, 1H), 4.04-3.97 (m, 2H), 3.94-3.84 (m, 2H), 3.77 (s, 3H), 3.06-2.95(m, 1H), 2.04 (s, 3H), 1.99-1.85 (m, 2H), 1.84-1.75 (m, 1H), 1.74-1.61(m, 1H), 1.57-1.45 (m, 1H), 1.17-1.06 (m, 2H), 0.98-0.86 (m, 1H),0.84-0.72 (m, 1H).

Example 879:(S)—N-(1-Formylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using steps A-B in Example 897, usingtert-butyl (S)-3-aminopiperidine-1-carboxylate in place of tert-butyl3-aminopiperidine-1-carboxylate in step A, using formic acid in place of(E)-2-cyano-4,4-dimethylpent-2-enoic acid in step B. MS (ESI): masscalcd. for C₂₈H₂₅N₅O₄S, 527.6; m/z found, 528.3[M+H]⁺. ¹H NMR (400 MHz,a mixture of DMSO-d₆ and CD₃OD): d 8.32-8.28 (m, 1H), 8.01-7.95 (m, 1H),7.43-7.35 (m, 2H), 7.33-7.28 (m, 1H), 7.18-7.12 (m, 1H), 7.10-7.02 (m,3H), 6.97-6.90 (m, 1H), 6.00-5.95 (m, 1H), 3.88-3.74 (m, 3H), 3.09-2.94(m, 1H), 2.73-2.60 (m, 1H), 2.06 (s, 3H), 2.00-1.91 (m, 1H), 1.82-1.71(m, 1H), 1.71-1.69 (m, 1H), 1.51-1.39 (m, 1H).

Example 880:(R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions to Example921, using(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 865) to afford a light yellow solid. MS (ESI): mass calcd. forC₃₅H₃₄N₆O₄S, 634.8; m/z found, 635.3 [M+H]⁺. ¹HNMR (400 MHz, a mixtureof DMSO-d₆ and CD₃OD): δ 8.30-8.26 (m, 1H), 7.41-7.34 (m, 2H), 7.32-7.26(m, 1H), 7.16-7.10 (m, 1H), 7.08-7.00 (m, 3H), 6.95-6.89 (m, 1H),6.78-6.74 (m, 1H), 5.97-5.92 (m, 1H), 3.93-3.77 (m, 3H), 3.13-3.07 (m,2H), 2.03 (s, 3H), 1.96-1.87 (m, 1H), 1.83-1.74 (m, 1H), 1.72-1.62 (m,1H), 1.56-1.43 (m, 1H), 1.22-1.12 (m, 9H).

Example 881:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: Methyl3-amino-4-((4-(pyridin-2-yloxy)phenyl)amino)thieno[2,3-b]pyridine-2-carboxylate

To a solution of 4-(pyridin-2-yloxy)aniline 3.00 g, 16.1 mmol) and2-chloro-4-iodopyridine-3-carbonitrile (5.539 g, 20.94 mmol) in dioxane(30 mL) were added DPEphos (1.735 g, 3.221 mmol), Pd(OAc)₂ (0.362 g,1.61 mmol), and Cs₂CO₃ (10.498 g, 32.222 mmol) under a N₂ atmosphere andwas stirred at 100° C. for 4 h. After 4 h, methyl 2-mercaptoacetate(2.565 g, 24.17 mmol) was and the reaction was stirred at 100° C.overnight. The reaction was filtered to remove the solid and wasconcentrated to dryness. MeOH was added to the residue with stirring andthe precipitate that formed was filtered. The precipitate was added toEtOAc, stirred, filtered, and dried under a vacuum to give the titlecompound (2.7 g, 43% yield) as a grey solid.

Step B:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsE-I in Example 1, and using methyl3-amino-4-((4-(pyridin-2-yloxy)phenyl)amino)thieno[2,3-b]pyridine-2-carboxylatein place of methyl3-amino-4-(2-methyl-4-phenoxyanilino)thieno[2,3-b]pyridine-2-carboxylatein step E, and using 1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one(Intermediate 5) in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₂N₆O₄S, 526.6; m/z found, 527.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.22 (s, 1H), 8.53-8.37 (m, 1H),8.32 (d, J=5.5 Hz, 1H), 8.27-8.18 (m, 1H), 7.97-7.86 (m, 1H), 7.53-7.42(m, 2H), 7.38-7.28 (m, 2H), 7.24-7.17 (m, 1H), 7.16-7.09 (m, 1H),6.66-6.53 (m, 1H), 6.19-6.11 (m, 1H), 6.04 (d, J=5.5 Hz, 1H), 5.72-5.62(m, 1H), 4.59-4.41 (m, 1H), 3.92-3.38 (m, 4H), 2.26-1.93 (m, 2H).

Example 882:N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example181, using5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) in place of(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860) to give a white solid. MS (ESI): mass calcd. forC₃₀H₂₆N₆O₄S, 566.6; m/z found, 567.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 10.17 (s, 1H), 8.30 (d, J=5.4 Hz, 1H), 8.11-8.06 (m, 1H), 7.45-7.41(m, 2H), 7.35 (d, J=8.5 Hz, 1H), 7.20-7.16 (m, 1H), 7.11-7.07 (m, 3H),6.98-6.95 (m, 1H), 5.94 (d, J=5.3 Hz, 1H), 4.33-4.02 (m, 1H), 4.01-3.96(m, 2H), 3.85-3.76 (m, 1H), 3.69-3.55 (m, 1H), 3.10-2.94 (m, 1H),2.79-2.62 (m, 1H), 2.05 (s, 3H), 1.93-1.90 (m, 1H), 1.75-1.70 (m, 1H),1.63-1.54 (m, 1H), 1.45-1.38 (m, 1H).

Example 883:N-(1-Cyanopiperidin-3-yl)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example890, and using5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 870) in place of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) to give a light yellow solid. MS (ESI): mass calcd. forC₂₉H₂₆N₆O₄S, 554.6; m/z found, 555.2 [M+H]⁺. ¹H NMR (400 MHz, a mixtureof CD₃OD and DMSO-d₆): δ 8.28 (d, J=5.2 Hz, 1H), 7.23-7.16 (m, 2H),7.15-7.04 (m, 2H), 7.01-6.92 (m, 1H), 6.87 (s, 1H), 6.79-6.73 (m, 1H),5.94 (d, J=5.3 Hz, 1H), 4.01-3.88 (m, 1H), 3.75 (s, 3H), 3.48-3.40 (m,1H), 3.30-3.23 (m, 1H), 3.00-2.88 (m, 2H), 2.02 (s, 3H), 1.94-1.86 (m,1H), 1.82-1.74 (m, 1H), 1.70-1.61 (m, 1H), 1.60-1.50 (m, 1H).

Example 884:N-(1-Cyanopiperidin-4-yl)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example890, and using5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 917) in place of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) to give a light yellow solid. MS (ESI): mass calcd. forC₂₉H₂₆N₆O₄S, 554.6; m/z found, 555.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 10.12 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.08-7.98 (m, 1H), 7.28-7.17(m, 3H), 7.16-7.08 (m, 1H), 7.04-6.95 (m, 1H), 6.92-6.88 (m, 1H),6.81-6.72 (m, 1H), 5.90 (d, J=5.4 Hz, 1H), 3.98-3.88 (m, 1H), 3.76 (s,3H), 3.43-3.35 (m, 2H), 3.16-3.06 (m, 2H), 2.01 (s, 3H), 1.85-1.75 (m,2H), 1.74-1.61 (m, 2H).

Example 885:(R)—N-(1-Formylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared by treating(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) with formic acid and allowing the mixture to stir at roomtemperature for 5 hours. The mixture was purified by ISCO (MeOH/H₂O). MS(ESI): mass calcd. for C₂₈H₂₅N₅O₄S, 527.6; m/z found, 528.3[M+H]⁺. ¹HNMR (400 MHz, a mixture of DMSO-d₆ and CD₃OD): δ 8.27-8.21 (m, 1H),7.98-7.90 (m, 1H), 7.39-7.31 (m, 2H), 7.28-7.21 (m, 1H), 7.14-7.07 (m,1H), 7.05-6.97 (m, 3H), 6.93-6.86 (m, 1H), 5.94-5.88 (m, 1H), 3.82-3.68(m, 2H), 3.14-3.08 (m, 1H), 3.05-2.92 (m, 1H), 2.72-2.60 (m, 1H), 2.02(s, 3H), 1.96-1.87 (m, 1H), 1.78-1.67 (m, 1H), 1.67-1.65 (m, 1H),1.47-1.35 (m, 1H).

Example 886:(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:4-Oxo-N-(piperidin-3-yl)-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 61)

The title compound was prepared in a manner analogous to Method 1, stepG-H in Example 1, using using4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 54) and tert-butyl-3-aminopiperidine-1-carboxylate inplace of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate.

Step B:(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions to Example877, and using4-oxo-N-(piperidin-3-yl)-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 61) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) to give a white solid. MS (ESI): mass calcd. forC₂₈H₂₆N₆O₃S, 526.6; m/z found, 527.4 [M+H]⁺. ¹H NMR (400 MHz, a mixtureof CD₃OD and DMSO-d₆): δ 8.27 (d, J=4.7 Hz, 1H), 7.57-7.23 (m, 4H),6.57-6.41 (m, 1H), 5.86 (d, J=4.5 Hz, 1H), 3.93-3.83 (m, 2H), 3.82-3.72(m, 1H), 3.11-2.87 (m, 2H), 2.10 (s, 3H), 2.01-1.88 (m, 2H), 1.85-1.76(m, 1H), 1.74-1.62 (m, 1H), 1.59-1.46 (m, 1H), 1.19-1.05 (m, 2H),1.00-0.89 (m, 1H), 0.86-0.73 (m, 1H).

Example 887:(S)—N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example890, and using(S)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 912) in place of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) to give a light yellow solid. MS (ESI): mass calcd. forC₂₈H₂₄N₆O₃S, 524.6; m/z found, 525.3[M+H]⁺. ¹H NMR (400 MHz, a mixtureof DMSO-d₆ and CD₃OD): δ 8.34-8.30 (m, 1H), 7.44-7.37 (m, 2H), 7.35-7.30(m, 1H), 7.20-7.13 (m, 1H), 7.12-7.03 (m, 3H), 6.99-6.92 (m, 1H),6.01-5.96 (m, 1H), 4.02-3.94 (m, 1H), 3.47-3.40 (m, 1H), 3.33-3.24 (m,1H), 3.01-2.91 (m, 2H), 2.06 (s, 3H), 1.95-1.84 (m, 1H), 1.83-1.74 (m,1H), 1.70-1.50 (m, 2H).

Example 888:(R)—N-(1-Acetylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, using(R)-4-oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 911) in placeN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,and using acetyl chloride in place of prop-2-enoyl chloride. MS (ESI):mass calcd. for C₂₇H₂₃N₅O₄S, 513.6; m/z found, 514.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 10.11 (s, 1H), 8.41-8.15 (m, 2H), 7.52-7.34 (m, 4H),7.25-7.01 (m, 5H), 6.05 (dd, J=5.4, 1.9 Hz, 1H), 4.50-4.37 (m, 1H),3.77-3.71 (m, 1H), 3.59-3.54 (m, 1H), 3.49-3.41 (m, 2H), 2.23-1.96 (m,2H), 1.92 (d, J=5.0 Hz, 3H).

Example 889:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG-H, in Example 1, using tert-butyl 3-aminopiperidine-1-carboxylate inplace of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G, and using 2,2,2-trifluoroacetic acid inplace of HCl aq solution in step H was isolated as a white solid. MS(ESI): mass calcd. for C₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.1 [M+H]+. ¹HNMR (400 MHz, CD₃OD): δ 8.27-8.15 (br, 1H), 7.37-7.33 (m, 2H), 7.21-7.19(m, 1H), 7.13-7.09 (m, 1H), 7.06-6.99 (m, 3H), 6.94-6.91 (m, 1H),5.96-5.88 (m, 1H), 4.15-4.09 (m, 1H), 3.29-3.26 (m, 1H), 3.05-3.02 (m,1H), 2.83-2.76 (m, 2H), 2.07 (s, 3H), 2.03-1.97 (m, 1H), 1.93-1.83 (m,1H), 1.72-1.64 (m, 2H).

Example 890:N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To the mixture of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889), DIEA in DCM was added cyanic bromide at 0° C., thenstirred at room temperature for 2 hours. The mixture was concentratedand purified by ISCO, eluting with DCM/MeOH to yield the title product.MS (ESI): mass calcd. for C₂₈H₂₄N₆O₃S, 524.6; m/z found, 525.2 [M+H]+.¹H NMR (400 MHz, a mixture of CD3OD and DMSO-d₆): δ 8.26 (d, J=5.5 Hz,1H), 7.38-7.31 (m, 2H), 7.28-7.24 (m, 1H), 7.14-7.08 (m, 1H), 7.06-6.98(m, 3H), 6.93-6.87 (m, 1H), 5.96 (d, J=5.5 Hz, 1H), 4.01-3.97 (m, 1H),3.47-3.40 (m, 1H), 3.29-3.21 (m, 1H), 2.99-2.87 (m, 2H), 2.03 (s, 3H),1.92-1.85 (m, 1H), 1.80-1.72 (m, 1H), 1.69-1.59 (m, 1H), 1.56-1.48 (m,1H).

Example 891:(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5, 8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example 75and using(S)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 912) and propionic acid in place of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) and 3-hydroxypropanoic acid to give a white solid. MS(ESI): mass calcd. for C₃₀H₂₉N₅O₄S, 555.7; m/z found, 556.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 10.18 (br, 1H), 8.43-8.33 (m, 1H), 8.21-8.15(br, 1H), 7.42-7.38 (m, 2H), 7.26-7.24 (m, 1H), 7.17-7.03 (m, 4H),6.93-6.91 (m, 1H), 5.82-5.76 (br, 1H), 4.36-4.04 (m, 1H), 3.88-3.67 (m,2H), 3.05-2.91 (m, 1H), 2.77-2.55 (m, 1H), 2.37-2.22 (m, 2H), 2.01 (s,3H), 1.91-1.85 (m, 1H), 1.79-1.53 (m, 2H), 1.47-1.30 (m, 1H), 1.04-0.90(m, 3H).

Example 892:(S)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example 75and using(S)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 912) and 2-cyanoacetic acid in place of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) and 3-hydroxypropanoic acid to give a white solid. MS(ESI): mass calcd. for C₃₀H₂₆N₆O₄S, 566.6; m/z found, 567.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 8.78-8.69 (m, 1H), 8.09 (d, J=5.4 Hz, 1H),7.43-7.37 (m, 2H), 7.19-7.13 (m, 2H), 7.11-7.05 (m, 2H), 7.01 (d, J=2.4Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 5.70-5.66 (m, 1H), 4.22-4.07 (m, 1H),4.05-3.98 (m, 1H), 4.01-3.94 (m, 1H), 3.86-3.78 (m, 1H), 3.66-3.41 (m,1H), 3.14 (s, 2H), 3.10-2.97 (m, 1H), 2.01 (s, 3H), 1.91-1.82 (m, 1H),1.71-1.63 (m, 1H), 1.59-1.49 (m, 1H).

Example 893:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((S)-pyrrolidine-2-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example 75and using (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid inplace of 3-hydroxypropanoic acid to give a yellow solid. MS (ESI): masscalcd. for C₃₂H₃₂N₆O₄S, 596.7; m/z found, 597.2 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.34-8.28 (m, 1H), 7.44-7.35 (m, 2H), 7.32-7.25 (m, 1H),7.20-7.13 (m, 1H), 7.10-7.02 (m, 3H), 7.00-6.93 (m, 1H), 6.08-6.02 (m,1H), 4.71-4.64 (m, 1H), 4.51-4.26 (m, 1H), 4.09-3.76 (m, 2H), 3.47-3.33(m, 2H), 3.22-3.06 (m, 1H), 2.95-2.87 (m, 1H), 2.58-1.47 (m, 11H).

Example 894:(R)—N-(1-Acryloylpiperidin-3-5((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsG-I, in Example 1, using5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 75) and tert-butyl(R)-3-aminopiperidine-1-carboxylate in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₃₈H₃₂N₆O₅S, 684.8; m/z found, 685.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.30 (br, 1H), 8.49-8.13 (m, 2H),7.74-7.67 (m, 1H), 7.66-7.61 (m, 1H), 7.49-7.42 (m, 1H), 7.35-7.23 (m,3H), 7.23-7.19 (m, 1H), 7.10-7.03 (m, 3H), 6.99-6.92 (m, 1H), 6.82-6.67(m, 1H), 6.10-6.01 (m, 1H), 5.95-5.86 (m, 1H), 5.68-5.60 (m, 1H), 5.31(s, 2H), 4.45-4.11 (m, 1H), 4.05-3.87 (m, 1H), 3.82-3.68 (m, 1H),3.11-2.91 (m, 1H), 2.82-2.61 (m, 1H), 2.01 (s, 3H), 1.94-1.88 (m, 1H),1.78-1.58 (m, 2H), 1.43-1.35 (m, 1H).

Example 895:(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example835, steps A-B, using tert-butyl (S)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (R)-3-aminopiperidine-1-carboxylate. MS (ESI): masscalcd. for C₃₅H₂₉F₃N₈O₄S, 714.7; m/z found, 715.4 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 11.35 (s, 1H), 10.98-10.02 (br, 1H), 8.66 (d, J=5.1 Hz,1H), 8.53 (s, 1H), 8.30 (d, J=5.4 Hz, 1H), 8.25-8.07 (m, 2H), 8.02 (d,J=8.1 Hz, 1H), 7.65-7.39 (m, 2H), 6.62-6.52 (m, 1H), 5.88 (d, J=5.4 Hz,1H), 4.40-3.97 (m, 1H), 3.95-3.70 (m, 2H), 3.17-2.72 (m, 2H), 2.17 (s,3H), 2.04-1.73 (m, 3H), 1.72-1.56 (m, 1H), 1.55-1.32 (m, 1H), 1.22-1.09(m, 2H), 1.01-0.70 (m, 2H).

Example 896:(E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example398, Step C, using5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 870) in place of (R)-tert-butyl3-(5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate.MS (ESI): mass calcd. for C₃₆H₃₆N₆O₅S, 664.8; m/z found, 665.2 [M+H]⁺.¹H NMR (400 MHz, a mixture of CD₃OD and DMSO-d₆): δ 8.28 (d, J=5.5 Hz,1H), 7.24-7.16 (m, 2H), 7.15-7.11 (m, 1H), 7.09-7.05 (m, 1H), 7.00-6.93(m, 1H), 6.90-6.85 (m, 1H), 6.80-6.71 (m, 2H), 5.93 (d, J=5.5 Hz, 1H),3.92-3.80 (m, 5H), 3.75 (s, 3H), 2.07-1.91 (m, 4H), 1.86-1.76 (m, 1H),1.74-1.61 (m, 1H), 1.58-1.45 (m, 1H), 1.25-1.15 (m, 9H).

Example 897:(E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enol)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example398, step D, using5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) in place of(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 300) a dark grey solid. MS (ESI): mass calcd. for C₃₅H₃₄N₆O₄S,634.8; m/z found, 635.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.34 (d,J=5.4 Hz, 1H), 8.17-8.12 (m, 1H), 7.49-7.42 (m, 2H), 7.39-7.35 (m, 1H),7.24-7.18 (m, 1H), 7.16-7.08 (m, 3H), 7.02-6.96 (m, 1H), 6.88-6.84 (m,1H), 5.98 (d, J=5.4 Hz, 1H), 3.94-3.85 (m, 2H), 3.41-3.36 (m, 2H),3.15-3.05 (m, 1H), 2.07 (s, 3H), 2.01-1.93 (m, 1H), 1.84-1.78 (m, 1H),1.76-1.66 (m, 1H), 1.58-1.50 (m, 1H), 1.25-1.21 (m, 9H).

Example 898:5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG, in Example 1, using 1-methylpiperidin-3-amine in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate as a white solid. MS(ESI): mass calcd. for C₂₈H₂₇N₅O₃S, 513.6; m/z found, 514.2 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.26 (d, J=5.6 Hz, 1H), 7.39-7.31 (m, 2H), 7.24(d, J=8.6 Hz, 1H), 7.14-7.10 (m, 1H), 7.07-6.99 (m, 3H), 6.95-6.92 (m,1H), 6.00 (d, J=5.6 Hz, 1H), 4.15-4.10 (m, 1H), 2.92-2.90 (m, 1H),2.71-2.68 (m, 1H), 2.32 (s, 3H), 2.24-2.18 (m, 2H), 2.08 (s, 3H),1.88-1.75 (m, 2H), 1.68-1.64 (m, 1H), 1.53-1.43 (m, 1H).

Example 899:(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example877, and using(S)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 912) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) to give a dark grey solid. MS (ESI): mass calcd. forC₃₄H₃₀N₆O₄S, 618.7; m/z found, 619.2 [M+H]⁺. ¹H NMR (400 MHz, a mixtureof CD₃OD and DMSO-d₆): δ 8.30-8.26 (m, 1H), 7.39-7.33 (m, 2H), 7.29-7.24(m, 1H), 7.15-7.09 (m, 1H), 7.08-7.00 (m, 3H), 6.94-6.89 (m, 1H),6.49-6.43 (m, 1H), 6.00-5.96 (m, 1H), 4.14-4.10 (m, 1H), 3.96-3.83 (m,2H), 3.11-2.92 (m, 2H), 2.05 (s, 3H), 1.98-1.86 (m, 2H), 1.82-1.75 (m,1H), 1.72-1.62 (m, 1H), 1.57-1.46 (m, 1H), 1.16-1.08 (m, 2H), 0.95-0.87(m, 1H), 0.82-0.73 (m, 1H).

Example 900:(R,E)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(4-(piperidin-1-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example 75and using (E)-4-(piperidin-1-yl)but-2-enoic acid in place of3-hydroxypropanoic acid. MS (ESI): mass calcd. for C₃₆H₃₈N₆O₄S, 650.8;m/z found, 651.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.24 (br, 1H),8.40-8.32 (m, 1H), 8.25-8.09 (m, 1H), 7.49-7.42 (m, 2H), 7.42-7.35 (m,1H), 7.24-7.18 (m, 1H), 7.16-7.08 (m, 3H), 7.02-6.97 (m, 1H), 6.97-6.77(m, 1H), 6.75-6.61 (m, 1H), 6.03-5.97 (m, 1H), 4.50-4.15 (m, 1H),4.05-3.96 (m, 1H), 3.89-3.67 (m, 3H), 3.27-2.61 (m, 6H), 2.07 (s, 3H),1.98-1.92 (m, 1H), 1.86-1.56 (m, 7H), 1.51-1.35 (m, 2H).

Example 901:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-3-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example877, and using(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) to give a light yellow solid. MS (ESI): mass calcd. forC₃₄H₃₀N₆O₄S, 618.7; m/z found, 619.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 10.19 (s, 1H), 8.33 (d, J=5.4 Hz, 1H), 8.13 (d, J=6.9 Hz, 1H),7.45-7.32 (m, 3H), 7.28-7.19 (m, 1H), 7.15-7.02 (m, 2H), 7.00-6.94 (m,2H), 6.59-6.53 (m, 1H), 5.99 (d, J=5.4 Hz, 1H), 4.14-3.77 (m, 3H),3.09-2.75 (m, 2H), 1.95 (s, 3H), 1.93-1.62 (m, 4H), 1.53-1.42 (m, 1H),1.17-1.07 (m, 2H), 1.00-0.80 (m, 2H).

Example 902:(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-fluoro-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example836, steps A-B, using tert-butyl (S)-3-aminopiperidine-1-carboxylate inplace of tert-butyl (R)-3-aminopiperidine-1-carboxylate. MS (ESI): masscalcd. for C₃₄H₂₆F₄N₈O₄S, 718.7; m/z found, 719.3 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 11.50 (s, 1H), 10.39 (s, 1H), 8.68 (d, J=5.1 Hz, 1H),8.52 (s, 1H), 8.35 (d, J=5.5 Hz, 1H), 822-8.11 (m, 2H), 8.08-8.02 (m,1H), 7.85-7.75 (m, 1H), 7.55 (d, J=5.1 Hz, 1H), 6.62-6.52 (m, 1H),6.18-6.11 (m, 1H), 4.19-3.74 (m, 3H), 3.10-2.77 (m, 2H), 1.98-1.75 (m,3H), 1.71-1.58 (m, 1H), 1.54-1.38 (m, 1H), 1.19-1.10 (m, 2H), 1.03-0.91(m, 1H), 0.87-0.71 (m, 1H).

Example 903:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example 75and using5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) and propionic acid in place of(R)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 869) and 3-hydroxypropanoic acid. MS (ESI): mass calcd. forC₃₀H₂₉N₅O₄S, 555.7; m/z found, 556.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.28 (d, J=5.5 Hz, 1H), 7.39-7.33 (m, 2H), 7.25 (d, J=8.6 Hz, 1H),7.15-7.10 (m, 1H), 7.08-7.00 (m, 3H), 6.95-6.92 (m, 1H), 6.02 (d, J=5.5Hz, 1H), 4.46-4.25 (m, 1H), 4.04-3.76 (m, 2H), 3.16-2.99 (m, 1H),2.81-2.74 (m, 1H), 2.50-2.32 (m, 2H), 2.09 (s, 3H), 2.04-2.00 (m, 1H),1.84-1.65 (m, 2H), 1.54-1.48 (m, 1H), 1.10 (t, J=7.3 Hz, 3H).

Example 904:(S,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example921, and using(S)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 912) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 865). MS (ESI): mass calcd. for C₃₅H₃₄N₆O₄S, 634.8; m/z found,635.3[M+H]⁺. ¹H NMR (400 MHz, a mixture of DMSO-d₆ and CD₃OD): δ8.30-8.26 (m, 1H), 7.41-7.34 (m, 2H), 7.32-7.26 (m, 1H), 7.16-7.10 (m,1H), 7.08-7.00 (m, 3H), 6.95-6.89 (m, 1H), 6.78-6.74 (m, 1H), 5.97-5.92(m, 1H), 3.93-3.77 (m, 3H), 3.13-3.07 (m, 2H), 2.05-2.03 (m, 3H),1.96-1.87 (m, 1H), 1.83-1.74 (m, 1H), 1.72-1.62 (m, 1H), 1.56-1.43 (m,1H), 1.22-1.12 (m, 9H).

Example 905:(S,E)-N-(1-(2-Cyano-3-cyclopropylacrylol)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example877, and(S)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 71) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) to give a light yellow solid. MS (ESI): mass calcd. forC₃₃H₂₈N₆O₄S, 604.7; m/z found, 605.2 [M+H]⁺. ¹H NMR (400 MHz, a mixtureof CD3OD and DMSO-d₆): δ 8.29 (d, J=5.5 Hz, 1H), 7.43-7.35 (m, 2H),7.32-7.26 (m, 1H), 7.18-7.11 (m, 1H), 7.10-7.01 (m, 3H), 6.96-6.90 (m,1H), 6.75-6.68 (m, 1H), 5.97 (d, J=5.5 Hz, 1H), 4.55-4.45 (m, 1H),3.99-3.86 (m, 1H), 3.85-3.77 (br, 1H), 3.76-3.66 (m, 1H), 3.64-3.55 (m,1H), 3.52-3.42 (m, 1H), 2.24-2.11 (m, 1H), 2.05 (s, 3H), 1.97-1.86 (m,1H), 1.22-1.16 (m, 2H), 0.93-0.87 (m, 2H).

Example 906:(R)—N-(1-(3-Chloropropanoyl)piperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG in Example 1, using4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 60) and(S)-1-(3-aminopiperidin-1-yl)-3-chloropropan-1-one in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate. MS (ESI): mass calcd.for C₂₈H₂₅ClN₆O₄S, 577.1; m/z found, 577.3 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 10.29-10.17 (m, 1H), 8.43-8.29 (m, 2H), 8.13-8.00 (m, 1H),7.70-7.57 (m, 2H), 7.50-7.42 (m, 2H), 7.27-7.15 (m, 3H), 6.23-6.16 (m,1H), 4.47-4.15 (m, 1H), 3.93-3.68 (m, 4H), 3.04-2.77 (m, 3H), 2.69-2.52(m, 1H), 1.97-1.85 (m, 1H), 1.77-1.57 (m, 2H), 1.49-1.31 (m, 1H).

Example 907:5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG, in Example 1, using5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 67) and 1-methylpiperidin-3-amine in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate to yield the titleproduct as a yellow solid. MS (ESI): mass calcd. for C₂₉H₂₉N₅O₄S, 543.6;m/z found, 544.2 [M+H]⁺. ¹H NMR (400 MHz, a mixture of CD3OD andDMSO-d₆): δ 8.26 (d, J=5.5 Hz, 1H), 7.23-7.16 (m, 2H), 7.16-7.10 (m,1H), 7.09-7.02 (m, 1H), 7.01-6.91 (m, 1H), 6.91-6.84 (m, 1H), 6.80-6.71(m, 1H), 5.91 (d, J=5.5 Hz, 1H), 4.02-3.97 (m, 1H), 3.75 (s, 3H),2.88-2.77 (m, 1H), 2.70-2.59 (m, 1H), 2.25 (s, 3H), 2.13-1.97 (m, 5H),1.81-1.66 (m, 2H), 1.63-1.50 (m, 1H), 1.45-1.33 (m, 1H).

Example 908:(R)—N-(1-(2-(Azetidin-1-yl)acetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)—N-(1-(2-chloroacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 396) (150 mg, 0.26 mmol) in DCM was added trimethylamine.Azetidine (38 mg, 0.66 mmol) in DCM was added dropwise and was stirredat rt for 2 h. The reaction was concentrated to dryness and purified byflash column chromatography, then preparative TLC (DCM/MeOH; 20/1) togive the title compound (10 mg, 6%) as a yellow solid. MS (ESI): masscalcd. for C₃₂H₃₂N₆O₄S, 596.7; m/z found, 597.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 8.36-8.17 (m, 2H), 7.46-7.40 (m, 2H), 7.38-7.31 (m, 1H),7.21-7.16 (m, 1H), 7.13-7.06 (m, 3H), 7.00-6.92 (m, 1H), 5.99-5.89 (m,1H), 4.39-4.22 (m, 2H), 4.04-3.77 (m, 5H), 3.70-3.44 (m, 2H), 3.06-2.62(m, 2H), 2.39-2.21 (m, 2H), 2.04 (s, 3H), 1.95-1.88 (m, 1H), 1.79-1.62(m, 2H), 1.55-1.40 (m, 1H).

Example 909:4-Oxo-5-(4-phenoxyphenyl)-N-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG in Example 1, using4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 58) and tetrahydro-2H-pyran-4-amine in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate. MS (ESI): mass calcd.for C₂₆H₂₂N₄O₄S, 486.6; m/z found, 487.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 8.37-8.09 (m, 2H), 7.44-7.37 (m, 4H), 7.26-7.02 (m, 5H),6.00 (d, J=5.2 Hz, 1H), 4.05-3.94 (m, 1H), 3.86-3.84 (m, 2H), 3.09-2.93(m 2H), 1.75-1.72 (m, 2H), 1.58-1.56 (m, 2H).

Example 910:(R)—N-(1-Methylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To an oven dried microwave vial containing a stir bar under Ar wereadded(R)-4-oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 911) (117 mg, 0.249 mmol), sodium cyanoborohydride (34 mg, 0.54mmol), and MeOH (3 mL). The flask was cooled to 0° C. in an ice bath andthen aqueous HCHO (0.0174 mL, 471.45 mmol) was added via a syringethrough the septum cap. The reaction was allowed to slowly warm to roomtemperature and was stirred for an additional 30 min. The reactionmixture was filtered through a syringe filter and purified by flashcolumn chromatography to give the title compound (32.5 mg, 27.0% yield).MS (ESI): mass calcd. for C₂₆H₂₃N₅O₃S, 485.6; m/z found, 486.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): δ 8.43-8.23 (m, 1H), 7.48-7.35 (m, 2H),7.33-7.27 (m, 1H), 7.27-7.02 (m, 5H), 6.23-6.09 (m, 2H), 4.72-4.56 (m,1H), 3.06-2.94 (m, 1H), 2.85-2.74 (m, 1H), 2.66-2.52 (m, 3H), 2.47-2.36(m, 4H), 2.33-2.22 (m, 1H), 1.87-1.72 (m, 1H).

Example 911:(R)-4-Oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H in Example 1, and using 4-fluoronitrobenzene in place of5-fluoro-2-nitrotoluene in step A, and using Pt/C and THF in place ofFe, EtOH/H₂O, and NH₄Cl in step B, and using (R)-tert-butyl3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₅H₂₁N₅O₃S, 471.5; m/z found, 472.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.78 (d, J=6.1 Hz, 1H), 8.33 (s,1H), 8.21 (d, J=5.5 Hz, 1H), 7.44-7.40 (m, 2H), 7.37-7.34 (m, 2H),7.19-7.07 (m, 5H), 5.96 (d, J=5.5 Hz, 1H), 4.54-4.48 (m, 1H), 3.40-3.22(m, 2H), 3.21-3.06 (m, 2H), 2.21-2.12 (m, 1H), 1.97-1.88 (m, 1H).

Example 912:(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG-H, in Example 1, using (S)-tert-butyl 3-aminopiperidine-1-carboxylatein place of tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G and using 2,2,2-trifluoroacetic acid in placeof HCl aq solution in step H, as a yellow solid. MS (ESI): mass calcd.for C₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 8.59 (s, 1H), 8.10-8.04 (m, 1H), 7.42-7.38 (m, 2H),7.17-7.13 (m, 2H), 7.10-7.04 (m, 2H), 7.01 (d, J=2.7 Hz, 1H), 6.93-6.87(m, 1H), 5.70-5.64 (m, 1H), 3.93-3.87 (m, 1H), 3.16-3.10 (m, 1H),2.97-2.90 (m, 1H), 2.67-2.52 (m, 2H), 1.99 (s, 3H), 1.93-1.85 (m, 1H),1.76-1.69 (m, 1H), 1.56-1.44 (m, 2H).

Example 913:(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compounds was prepared using(R)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 70) (200 mg, 0.43 mmol) and(E)-4-(dimethylamino)but-2-enoic acid (208 mg, 0.644 mmol) in anhydrousDMF (5 mL) were added HATU (245 mg, 0.644 mmol) and DIPEA (112 mg, 0.859mmol) and was stirred overnight at rt. The reaction was purified byflash column chromatography to give the title compound (171 mg, 69.0%yield) as a yellow solid. MS (ESI): mass calcd. for C₃₀H₃₆N₆O₄S, 576.7;m/z found, 577.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.34-8.28 (m, 1H),7.22-7.17 (m, 1H), 6.98-6.95 (m, 1H), 6.93-6.83 (m, 2H), 6.75-6.62 (m,1H), 6.06-6.00 (m, 1H), 4.69-4.62 (m, 1H), 4.54-4.26 (m, 1H), 4.22-3.87(m, 2H), 3.74-3.65 (m, 2H), 3.24-3.13 (m, 1H), 2.97-2.86 (m, 1H),2.73-2.66 (m, 6H), 2.12-2.01 (m, 4H), 1.92-1.83 (m, 1H), 1.82-1.65 (m,1H), 1.65-1.52 (m, 1H), 1.35-1.32 (m, 6H).

Example 914:(R)—N-(1-Benzoylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, using(R)-4-oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 911) and benzoyl chloride in place of prop-2-enoyl chloride. MS(ESI): mass calcd. for C₃₂H₂₅N₅O₄S, 575.6; m/z found, 576.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 10.19 (s, 1H), 8.35-8.25 (m, 2H), 7.52-7.38(m, 9H), 7.29-7.00 (m, 5H), 6.05 (s, 1H), 4.57-4.34 (m, 1H), 3.88-3.63(m, 2H), 3.53-3.46 (m, 2H), 2.26-1.93 (m, 2H).

Example 915:(R)-4-Oxo-5-(5-phenoxypyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a 2-5 mL Biotage microwave vial containing a stir bar were added5-phenoxypyridin-2-amine (137 mg, 0.736 mmol),2-chloro-4-iodonicotinonitrile (191.9 mg, 0.726 mmol), Pd(OAc)₂ (3.3 mg,0.0147 mmol), DPEPhos (12.6 mg, 0.0234 mmol), and Cs₂CO₃ (349 mg, 1.07mmol). The vial was sealed, dioxane (1.45 mL) was added, evacuated andflushed with argon (4×), and stirred at 150° C. under argon for 30 min.The reaction was cooled to room temperature, treated with (R)-tert-butyl3-(2-mercaptoacetamido)piperidine-1-carboxylate (Intermediate 22) (1.5mL, 0.49 M, 0.74 mmol) via syringe, evacuated and flushed with argon(4×), and stirred at 150° C. for 15 min. The reaction was cooled to roomtemperature, treated with solid CDI (477 mg, 2.94 mmol) in one portionunder air, resealed, evacuated and flushed with argon (4×), and stirredat 150° C. for 15 min. The reaction was diluted with EtOAc (10 mL),washed with 0.5 M citric acid in brine (2×8 mL), and 2 M K₂CO₃ (1×5 mL).The organic phase was dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness. The residue was dissolved in ˜5 mL DCM andpurified by flash column chromatography to yield the title compound(120.7 mg, 28.35% yield). MS (ESI): mass calcd. for C₃₀H₃₀N₆O₅S, 586.67;m/z found, 587.3 [M+H]⁺.

Step B:(R)-4-Oxo-5-(5-phenoxypyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(120.7 mg, 0.206 mmol) in dioxane (1 mL) was treated with HCl (3.97 M indioxane, 2.60 mL, 10.3 mmol) in one portion at room temperature, and wasstirred at room temperature for 1 h. The reaction was then concentratedto dryness and was purified (19.1 mg of the di-HCl salt) by C18 HPLC(30×100 mm Phenomenex Kinetex column, 5 μm; mobile phase A: H₂O (0.1%TFA); B: acetonitrile (0.1% TFA), gradient: B in A from 10% to 90%) togive the title compound as a yellow-beige powder (19.7 mg, 13.4% yield).MS (ESI): mass calcd. for C₂₅H₂₂N₆O₃S, 486.6; m/z found, 487.2 [M+H]⁺.¹H NMR (400 MHz, MeOH) δ 8.39 (d, J=2.53 Hz, 1H), 8.37 (d, J=5.56 Hz,1H), 7.61-7.67 (m, 1H), 7.55-7.60 (m, 1H), 7.44-7.52 (m, 2H), 7.24-7.30(m, 1H), 7.16-7.22 (m, 2H), 6.28 (d, J=6.06 Hz, 1H), 4.19-4.33 (m, 1H),3.51-3.57 (m, 1H), 3.36 (br d, J=12.63 Hz, 1H), 2.89-3.02 (m, 2H),2.02-2.15 (m, 2H), 1.67-1.91 (m, 2H).

Example 916:(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example877, using5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 865) in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) to give a light yellow solid. MS (ESI): mass calcd. forC₃₄H₃₀N₆O₄S, 618.7; m/z found, 619.2 [M+H]⁺. ¹H NMR (400 MHz, a mixtureof CD3OD and DMSO-d₆): δ 8.29 (d, J=5.5 Hz, 1H), 7.42-7.35 (m, 2H),7.31-7.26 (m, 1H), 7.17-7.11 (m, 1H), 7.09-7.01 (m, 3H), 6.96-6.90 (m,1H), 6.51-6.45 (m, 1H), 5.96 (d, J=5.5 Hz, 1H), 4.09-4.03 (m, 1H),3.79-3.73 (m, 2H), 3.10-2.93 (m, 2H), 2.05 (s, 3H), 1.93-1.85 (m, 3H),1.62-1.51 (m, 2H), 1.19-1.13 (m, 2H), 0.89-0.83 (m, 2H).

Example 917:5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG-H, in Example 1, using5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 67) and tert-butyl 4-aminopiperidine-1-carboxylate inplace of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate to yield the titleproduct as a light yellow solid. MS (ESI): mass calcd. for C₂₈H₂₇N₅O₄S,529.6; m/z found, 530.2 [M+H]⁺. ¹H NMR (400 MHz, a mixture of CD₃OD andDMSO-d₆): δ 8.11 (d, J=5.5 Hz, 1H), 7.21-7.04 (m, 4H), 6.98-6.92 (m,1H), 6.87-6.82 (m, 1H), 6.76-6.70 (m, 1H), 5.75 (d, J=5.5 Hz, 1H),4.01-3.96 (m, 1H), 3.75 (s, 3H), 3.23-3.17 (m, 2H), 2.91-2.81 (m, 2H),2.02-1.94 (m, 5H), 1.74-1.61 (m, 2H).

Example 918:5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG, in Example 1, using5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 67) and 1-methylpiperidine-4-amine in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate as a yellow solid. MS(ESI): mass calcd. for C₂₉H₂₉N₅O₄S, 543.6; m/z found, 544.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 8.26 (d, J=5.4 Hz, 1H), 8.14-8.05 (m, 1H),7.26-7.16 (m, 3H), 7.11-7.08 (m, 1H), 7.02-6.95 (m, 1H), 6.92-6.85 (m,1H), 6.79-6.73 (m, 1H), 5.85 (d, J=5.4 Hz, 1H), 3.76-3.72 (m, 4H),2.87-2.80 (m, 2H), 2.23 (s, 3H), 2.14-2.05 (m, 2H), 2.00 (s, 3H),1.82-1.72 (m, 2H), 1.68-1.56 (m, 2H).

Example 919:(R)-5-(4-(Cyclopentyloxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H, and using 4-(cyclopentyloxy)-2-methylaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₆H₂₉N₅O₃S, 491.6; m/z found, 492.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.33-8.26 (m, 1H), 7.15-7.05 (m, 1H),6.91-6.79 (m, 2H), 6.64-6.47 (m, 1H), 5.99-5.93 (m, 1H), 4.81-4.73 (m,1H), 4.30-4.19 (m, 1H), 3.23-3.15 (m, 1H), 3.02-2.87 (m, 3H), 2.13-2.09(m, 3H), 1.94-1.77 (m, 9H), 1.68-1.58 (m, 3H).

Example 920:N-(1-Methylpiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared by treating4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 58, 160 mg, 0.40 mmol) in DCM (10 mL) was addedoxalyl chloride (100 mg, 0.80 mmol) and 1 drop of DMF, then was stirredat 40° C. for 2 hours. After concentration under vacuo to dryness, theresidue was dissolved in DCM (10 mL) and was added a solution of1-methylpiperidin-4-amine (90 mg, 0.80 mmol) in DCM (5 mL), stirred atroom temperature for 5 minutes. The mixture was concentrated andpurified by ISCO using MeOH/water as eluent to yield the title productas a yellow solid (129 mg, 67% yield). MS (ESI): mass calcd. forC₂₇H₂₅N₅O₃S, 499.6; m/z found, 500.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 8.24-8.20 (m, 3H), 7.50-7.31 (m, 4H), 7.19-7.09 (m, 5H), 5.96 (d,J=5.5 Hz, 1H), 3.75-3.73 (m, 1H), 2.82-2.79 (m, 2H), 2.20 (s, 3H),2.09-2.04 (m, 2H), 1.81-1.73 (m, 2H), 1.63-1.55 (m, 2H).

Example 921:(E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 865) (100 mg, 0.18 mmol), (E)-2-cyano-4,4-dimethylpent-2-enoicacid (Intermediate 44) (57 mg, 0.37 mmol), DIEA (40 mg, 0.27 mmol), HATU(91 mg, 0.24 mmol), and DMF (5 mL). The reaction mixture was stirred atroom temperature for 5 hours. The mixture was purified by ISCO(MeOH/H₂O) to yield the title compound (20 mg, 18% yield) as a yellowsolid. MS (ESI): mass calcd. for C₃₅H₃₄N₆O₄S, 634.8; m/z found, 635.2[M+H]⁺. ¹H NMR (400 MHz, a mixture of CD₃OD and DMSO-d₆): δ 8.29 (d,J=5.5 Hz, 1H), 7.42-7.34 (m, 2H), 7.31-7.27 (m, 1H), 7.17-7.11 (m, 1H),7.09-7.01 (m, 3H), 6.96-6.91 (m, 1H), 6.76-6.73 (m, 1H), 5.98 (d, J=5.5Hz, 1H), 4.25-4.21 (m, 1H), 4.14-4.06 (m, 2H), 3.89-3.83 (m, 2H), 2.05(s, 3H), 1.96-1.87 (m, 2H), 1.63-1.52 (m, 2H), 1.24-1.20 (m, 9H).

Example 922:(R)-4-Oxo-5-(6-phenoxypyridin-3-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(4-oxo-5-(6-phenoxypyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

To a 2-5 mL Biotage microwave vial containing a stir bar were added6-phenoxypyridin-3-amine (182.5 mg, 0.0.9800 mmol),2-chloro-4-iodonicotinonitrile (256.8 mg, 0.7260 mmol), Pd(OAc)₂ (4.7mg, 0.021 mmol), DPEPhos (15.6 mg, 0.0290 mmol), and Cs₂CO₃ (446 mg,1.37 mmol). The vial was sealed, dioxane (1.95 mL) was added, evacuatedand flushed with argon (4×), and stirred at 150° C. under argon for 30min. The reaction was cooled to room temperature, treated with(R)-tert-butyl 3-(2-mercaptoacetamido)piperidine-1-carboxylate(Intermediate 22) (2.0 mL, 0.49 M, 0.98 mmol) via syringe, evacuated andflushed with argon (4×), and stirred at 150° C. for 15 min. The reactionwas cooled to room temperature, treated with solid CDI (628 mg, 3.87mmol) in one portion under air, resealed, evacuated and flushed withargon (4×), and stirred at 150° C. for 15 min. The reaction was dilutedwith EtOAc (10 mL), washed with 0.5 M citric acid in brine (2×8 mL), and2 M K₂CO₃ (1×5 mL). The organic phase was dried over anhydrous Na₂SO₄,filtered, and concentrated to dryness. The residue was dissolved in ˜5mL DCM and purified by flash column chromatography to yield the titlecompound (328.5 mg, 57.66% yield). MS (ESI): mass calcd. forC₃₀H₃₀N₆O₅S, 586.67; m/z found, 587.1 [M+H]⁺.

Step B:(R)-4-Oxo-5-(6-phenoxypyridin-3-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(4-oxo-5-(6-phenoxypyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(323.5 mg, 0.551 mmol) in dioxane (2.7 mL) was treated with HCl (3.97 Min dioxane, 6.90 mL, 27.4 mmol) in one portion at room temperature, andwas stirred at room temperature for 1 h. The reaction was thenconcentrated to dryness and was purified (24.7 mg of the di-HCl salt) byC18 HPLC (30×100 mm Phenomenex Kinetex column, 5 μm; mobile phase A: H₂O(0.1% TFA); B: acetonitrile (0.1% TFA), gradient: B in A from 10% to90%) to give the title compound as a light yellow-powder (16.1 mg, 4.09%yield). MS (ESI): mass calcd. for C₂₅H₂₂N₆O₃S, 486.6; m/z found, 487.2[M+H]+. ¹H NMR (400 MHz, MeOH) δ 8.38 (d, J=5.56 Hz, 1H), 8.21 (s, 1H),7.86-7.96 (m, 1H), 7.39-7.50 (m, 2H), 7.23-7.30 (m, 1H), 7.14-7.23 (m,3H), 6.29 (d, J=5.56 Hz, 1H), 4.19-4.34 (m, 1H), 3.51-3.57 (m, 1H), 3.36(br d, J=13.14 Hz, 1H), 2.94 (q, J=11.12 Hz, 2H), 2.02-2.15 (m, 2H),1.67-1.92 (m, 2H).

Example 923:(R)-5-(4-Isopropoxy-2-methylphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 70) (200 mg, 0.43 mmol) and2-((tert-butoxycarbonyl)(methyl)amino)acetic acid (305 mg, 0.644 mmol)in anhydrous DMF (5 mL) were added HATU (245 mg, 0.644 mmol) and DIPEA(112 mg, 0.859 mmol) and was stirred overnight at rt. The reaction waspurified by flash column chromatography to give the title compound (107mg, 46.4% yield) as a yellow solid. MS (ESI): mass calcd. forC₂₇H₃₂N₆O₄S, 536.6; m/z found, 537.2 [M+H]+. ¹H NMR (400 MHz, CD₃OD): δ8.15-8.08 (m, 1H), 7.15-7.06 (m, 1H), 6.98-6.92 (m, 1H), 6.92-6.85 (m,1H), 5.86-5.78 (m, 1H), 4.68-4.60 (m, 1H), 4.26-3.92 (m, 2H), 3.91-3.61(m, 3H), 3.59-3.33 (m, 2H), 2.59-2.51 (m, 3H), 2.11-2.07 (m, 3H),2.01-1.76 (m, 3H), 1.65-1.52 (m, 1H), 1.35-1.32 (m, 6H).

Example 924:(S)—N-(1-Acetylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, using(S)-4-oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 934) and acetyl chloride in place of prop-2-enoyl chloride. MS(ESI): mass calcd. for C₂₇H₂₃N₅O₄S, 513.6; m/z found, 514.2 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆): δ 10.09 (s, 1H), 8.34-8.28 (m, 2H), 7.53-7.32(m, 4H), 7.24-7.00 (m, 5H), 6.12-5.96 (m, 1H), 4.50-4.37 (m, 1H),3.83-3.65 (m, 1H), 3.56-3.52 (m, 1H), 3.49-3.41 (m, 2H), 2.21-1.95 (m,2H), 1.91 (d, J=5.1 Hz, 3H).

Example 925:(R)—N-(1-Benzylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)-4-oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 911) (150 mg, 0.318 mmol) was dissolved in DCM (30 mL),followed by the addition of NaBH(AcO)₃ (101 mg, 0.477 mmol) andbenzaldehyde (51 mg, 0.477 mmol). The reaction mixture was stirred atroom temperature under N₂ overnight. The mixture was washed with satNa₂CO₃ solution and concentrated, purified by flash columnchromatography eluting with water (0.5% HCOOH)/MeOH to yield the titleproduct as a white solid (115 mg, 64% yield). MS (ESI): mass calcd. forC₃₂H₂₇N₅O₃S, 561.6; m/z found, 561.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 8.29 (d, J=5.5 Hz, 1H), 8.21 (d, J=6.8 Hz, 1H), 8.11 (d, J=0.7 Hz,1H), 7.4-7.402 (m, 4H), 7.30-7.27 (m, 4H), 7.26-7.06 (m, 6H), 6.04 (d,J=5.5 Hz, 1H), 4.41-4.32 (m, 1H), 3.61 (s, 2H), 2.83-2.77 (m, 1H),2.69-2.60 (m, 1H), 2.55-2.49 m, 1H), 2.47-2.41 (m, 1H), 2.17-2.08 (m,1H), 1.86-1.79 (m, 1H).

Example 926:4-Oxo-5-(4-phenoxyphenyl)-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of tert-butyl4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(Example 627, 3.70 g, 6.32 mmol) in DCM (20 mL) was added TFA (106 mL)dropwise and was stirred at rt for 30 min. The reaction was concentratedto dryness and the residue was purified by flash column chromatographyto give the title compound (2.90 g, 94.5% yield) as an off white solid.MS (ESI): mass calcd. for C₂₆H₂₃N₅O₃S, 485.6; m/z found, 486.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): δ 8.56 (d, J=7.5 Hz, 1H), 8.27 (s, 1H), 8.17(d, J=5.5 Hz, 1H), 7.55-7.28 (m, 4H), 7.19-7.08 (m, 5H), 5.92 (d, J=5.5Hz, 1H), 4.06-3.98 (m, 1H), 3.25-3.22 (m, 2H), 2.96-2.90 (m, 2H),1.97-1.94 (m, 2H), 1.71-1.63 (m, 2H).

Example 927:4-Oxo-5-(4-phenoxyphenyl)-N-(2-(pyrrolidin-1-yl)ethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG in Example 1, using4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 58) and 2-(pyrrolidin-1-yl)ethan-1-amine in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₅N₅O₃S, 499.6; m/z found, 499.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.26 (d, J=5.5 Hz, 2H), 7.45-7.37(m, 4H), 7.20-7.08 (m, 5H), 6.01 (d, J=5.5 Hz, 1H), 2.70 (t, J=6.6 Hz,2H), 2.67-2.61 (m, 4H), 1.74-1.68 (m, 4H).

Example 928:4-Oxo-5-(4-phenoxyphenyl)-N-(2-(piperazin-1-yl)ethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG-H in Example 1, using4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 58) and tert-butyl4-(2-aminoethyl)piperazine-1-carboxylate in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₇H₂₆N₆O₃S, 514.6; m/z found, 514.8[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.82 (s, 1H), 8.08 (d, J=5.3 Hz,1H), 7.41 (m, 2H), 7.28 (d, J=8.2 Hz, 2H), 7.21-7.04 (m, 5H), 5.83 (d,J=5.2 Hz, 1H), 3.39-3.33 (m, 4H), 3.03-2.96 (m, 4H), 2.58-2.49 (m, 4H).

Example 929:N-(1-Acryloylpiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, using5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 865) to yield a white solid. MS (ESI): mass calcd. forC₃₀H₂₇N₅O₄S, 553.6; m/z found, 554.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ8.22-8.16 (m, 1H), 8.03 (d, J=7.4 Hz, 1H), 7.44-7.38 (m, 2H), 7.32-7.26(m, 1H), 7.20-7.14 (m, 1H), 7.12-7.06 (m, 2H), 7.07-7.02 (m, 1H),6.96-6.90 (m, 1H), 6.22-6.15 (m, 1H), 6.08-6.03 (m, 1H), 5.86-5.82 (m,1H), 5.56-5.53 (m, 1H), 4.15-4.04 (m, 2H), 3.91-3.86 (m, 1H), 3.17-3.12(m, 1H), 2.03 (s, 3H), 1.99-1.93 (m, 1H), 1.84-1.79 (m, 2H), 1.43-1.35(m, 2H).

Example 930:(S)-5-(2-methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(S)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 912) (50 mg, 0.10 mmol) in MeOH was added 37% HCHO aq solution(50 mg, 0.50 mmol), followed by addition of sodium triacetoxyborohydride(42 mg, 0.20 mmol). The reaction mixture was stirred at room temperaturefor 5.0 hours, concentrated and purified by flash column chromatographyeluting with water (0.5% HCOOH)/MeOH to yield the title product as awhite solid (42 mg, 81.71% yield). MS (ESI): mass calcd. forC₂₈H₂₇N₅O₃S, 513.6; m/z found, 514.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 8.77 (d, J=8.1 Hz, 1H), 7.96 (d, J=5.5 Hz, 1H), 7.45-7.33 (m, 2H),7.18-7.10 (m, 1H), 7.10-7.02 (m, 3H), 6.99 (s, 1H), 6.88 (d, J=8.4 Hz,1H), 5.53 (d, J=5.4 Hz, 1H), 3.93-3.83 (m, 1H), 2.78-2.69 (m, 1H), 2.13(s, 3H), 1.97 (s, 3H), 1.92-1.74 (m, 3H), 1.69-1.58 (m, 2H), 1.56-1.42(m, 2H).

Example 931:(S)—N-(1-Methylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(S)-4-oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 934) (150 mg, 0.32 mmol) in MeOH was added 37% HCHO aq solution(78 mg, 0.95 mmol), followed by addition of sodium borohydride (36 mg,0.95 mmol). The reaction mixture was stirred at room temperature for 2hours, concentrated and purified by flash column chromatography elutingwith water (0.5% HCOOH)/MeOH to yield the title product as a white solid(147 mg, 95% yield). MS (ESI): mass calcd. for C₂₆H₂₃N₅O₃S, 485.6; m/zfound, 486.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.37 (d, J=6.8 Hz,1H), 8.27 (d, J=5.5 Hz, 1H), 8.17 (s, 1H), 7.49-7.31 (m, 4H), 7.20-7.09(m, 5H), 6.02 (d, J=5.5 Hz, 1H), 4.46-4.38 (m, 1H), 2.90-2.79 (m, 2H),2.69-2.65 (m, 1H), 2.62-2.55 (m, 1H), 2.38 (s, 3H), 2.26-2.12 (m, 1H),1.88-1.79 (m, 1H).

Example 932:4-Oxo-5-(4-phenoxyphenyl)-N-(2-(piperidin-1-yl)ethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG in Example 1, using4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 58) and 2-(piperidin-1-yl)ethan-1-amine in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate. MS (ESI): mass calcd.for C₂₈H₂₇N₅O₃S, 513.6; m/z found, 513.8 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 8.28 (d, J=4.8 Hz, 1H), 8.16 (s, 1H), 7.46-7.37 (m, 4H),7.21-7.07 (m, 5H), 6.03 (d, J=4.9 Hz, 1H), 2.59-2.52 (m, 2H), 2.52-2.47(m, 4H), 1.54-1.46 (m, 4H), 1.39-1.34 (m, 2H).

Example 933:N-(2-Morpholinoethyl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG in Example 1, using4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 58) and 2-morpholinoethan-1-amine in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate. MS (ESI): mass calcd.for C₂₇H₂₅N₅O₄S, 515.6; m/z found, 515.8 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 8.29 (d, J=5.4 Hz, 1H), 8.11 (s, 1H), 7.47-7.37 (m, 4H),7.21-7.07 (m, 5H), 6.04 (d, J=5.5 Hz, 1H), 3.56-3.53 (m, 4H), 2.45-2.42(m, 2H), 2.42-2.36 (m, 4H).

Example 934:(S)-4-Oxo-5-(4-phenoxyphenl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG-H in Example 1, using4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 58) and tert-butyl(S)-3-aminopyrrolidine-1-carboxylate in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₅H₂₁N₅O₃S, 471.5; m/z found, 472.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.78 (s, 1H), 8.26 (s, 1H), 8.18(d, J=4.9 Hz, 1H), 7.50-7.27 (m, 4H), 7.19-7.09 (m, 5H), 5.93 (d, J=5.5Hz, 1H), 4.51-4.45 (m, 1H), 3.32-3.24 (m, 2H), 3.15-3.06 (m, 2H),2.22-2.13 (m, 1H), 1.95-1.86 (m, 1H).

Example 935:N-(2-(4-Methylpiperazin-1-yl)ethyl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG in Example 1, using4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 58) and 2-(4-methylpiperazin-1-yl)ethan-1-amine inplace of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G to yield a white solid. MS (ESI): mass calcd. for C₂₈H₂₈N₆O₃S,528.6; m/z found, 528.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.27 (d,J=5.2 Hz, 1H), 8.14 (s, 1H), 7.50-7.35 (m, 4H), 7.29-7.03 (m, 5H), 6.02(d, J=5.3 Hz, 1H), 3.38-3.29 (d, J=6.0 Hz, 4H), 2.45-2.40 (d, J=6.5 Hz,4H), 2.40-2.30 (br, 4H), 2.16 (s, 3H).

Example 936:(R)—N-(1-Acetylpiperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, and using(R)-5-(4-Isopropoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 70), acetyl chloride and DMF in place ofN-((3R,5R)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,prop-2-enoyl chloride and DCM. MS (ESI): mass calcd. for C₂₆H₂₉N₅O₄S,507.6; m/z found, 508.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.31-8.25 (m,1H), 7.25-7.16 (m, 1H), 6.98-6.94 (m, 1H), 6.94-6.87 (m, 1H), 6.04-5.99(m, 1H), 4.72-4.60 (m, 1H), 4.53-4.25 (m, 1H), 4.10-3.76 (m, 2H),3.17-3.00 (m, 1H), 2.81-2.67 (m, 1H), 2.17-2.08 (m, 6H), 2.08-1.98 (m,1H), 1.89-1.77 (m, 1H), 1.73-1.45 (m, 2H), 1.37-1.29 (m, 6H).

Example 937:(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(pyridin-3-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 3-(pyridin-3-yl)aniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G to yield the title compound as a white solid. MS (ESI): masscalcd. for C₂₅H₂₂N₆O₂S, 470.5; m/z found, 471.3 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ 8.90-8.83 (m, 1H), 8.59-8.51 (m, 1H), 8.33 (d, J=5.6 Hz, 1H),8.21-8.11 (m, 1H), 7.92-7.86 (m, 1H), 7.82-7.72 (m, 2H), 7.57-7.46 (m,2H), 6.22 (d, J=5.6 Hz, 1H), 4.33-4.22 (m, 1H), 3.60-3.46 (m, 1H),3.39-3.32 (m, 1H), 3.04-2.87 (m, 2H), 2.15-1.99 (m, 2H), 1.91-1.67 (m,2H).

Example 938:(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example877, and using(S)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 912) in place5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 889) to give a white solid. MS (ESI): mass calcd. forC₃₄H₃₀N₆O₄S, 618.7; m/z found, 619.4[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ8.31 (d, J=5.6 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.36-7.29 (m, 2H),7.12-7.05 (m, 2H), 7.05-6.98 (m, 3H), 6.56-6.44 (m, 1H), 6.06 (d, J=5.5Hz, 1H), 4.25-3.91 (m, 3H), 3.25-2.94 (m, 2H), 2.12 (s, 3H), 2.09-1.96(m, 2H), 1.92-1.83 (m, 1H), 1.78-1.54 (m, 2H), 1.22-1.13 (m, 2H),1.02-0.92 (m, 1H), 0.91-0.76 (m, 1H).

Example 939:(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using tert-butyl(S)-3-aminopiperidine-1-carboxylate in place of tert-butyl3-aminopiperidine-1-carboxylate in Example 851 as a white solid. MS(ESI): mass calcd. for C₃₃H₂₈N₆O₄S, 604.7; m/z found, 605.4[M+H]⁺. ¹HNMR (400 MHz, CD₃OD): d 8.29 (d, J=5.6 Hz, 1H), 7.59-7.53 (m, 1H),7.40-7.31 (m, 2H), 7.18-7.09 (m, 3H), 7.09-7.03 (m, 3H), 6.53 (d, J=11.0Hz, 1H), 6.17 (d, J=5.6 Hz, 1H), 4.30-3.92 (m, 3H), 3.25-2.92 (m, 2H),2.07-1.94 (m, 2H), 1.91-1.82 (m, 1H), 1.79-1.55 (m, 2H), 1.24-1.15 (m,2H), 1.02-0.92 (m, 1H), 0.90-0.79 (m, 1H).

Example 940:(S)—N-(1-benzoylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, using using(S)-4-oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 934) and benzoyl chloride. MS (ESI): mass calcd. forC₃₂H₂₅N₅O₄S, 575.6; m/z found, 576.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 8.42-8.20 (m, 2H), 7.60-7.34 (m, 9H), 7.25-7.03 (m, 5H), 6.05 (t,J=6.0 Hz, 1H), 4.56-4.34 (m, 1H), 3.83-3.63 (m, 2H), 3.57-3.47 (m, 2H),2.25-1.87 (m, 2H).

Example 941:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3,5-dichlorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 3,5-dichloroaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, to yield the title compound as a white solid. MS (ESI): masscalcd. for C₂₃H₁₉Cl₂N₅O₃S, 516.4; m/z found, 515.8 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 10.31 (d, J=15.7 Hz, 1H), 8.36 (d, J=5.5 Hz, 1H),8.14-8.10 (m, 1H), 7.87-7.86 (m, 1H), 7.72 (d, J=1.8 Hz, 2H), 6.86-6.74(m, 1H), 6.18 (d, J=5.3 Hz, 1H), 6.11 (d, J=16.5 Hz, 1H), 5.69 (d,J=11.0 Hz, 1H), 4.74-4.44 (m, 1H), 4.27-3.95 (m, 2H), 3.18-3.06 (m, 1H),3.02-2.96 (m, 1H), 1.96-1.93 (m, 1H), 1.80-1.77 (m, 1H), 1.73-1.58 (m,1H), 1.43 (brs, 1H).

Example 942:(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example886, steps A-B, using tert-butyl-3-(S)-aminopiperidine-1-carboxylate inplace of tert-butyl-3-aminopiperidine-1-carboxylate in step A. MS (ESI):mass calcd. for C₂₈H₂₆N₆O₃S, 526.2; m/z found, 527.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆): δ 10.14 (s, 1H), 8.30 (d, J=5.5 Hz, 1H), 8.04 (d, J=7.2Hz, 1H), 7.40 (m, 4H), 6.63-6.50 (m, 1H), 5.83 (d, J=5.5 Hz, 1H),4.17-3.99 (m, 1H), 3.98-3.78 (m, 2H), 3.07-2.73 (s, 2H), 2.08 (s, 3H),1.95-1.89 (m, 1H), 1.89-1.81 (m, 1H), 1.81-1.73 (m, 1H), 1.73-1.59 (m,1H), 1.55-1.40 (m, 1H), 1.18-1.09 (m, 2H), 1.03-0.92 (m, 1H), 0.87-0.78(m, 1H).

Example 943:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(dimethylamino)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-35,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using a method analogous to Example 75,using(R)-5-(3-(Dimethylamino)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 943) and acrylic acid. MS (ESI): mass calcd. for C₂₅H₂₆N₆O₃S,490.6; m/z found, 491 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.13 (d,J=14.6 Hz, 1H), 8.33 (d, J=5.5 Hz, 1H), 8.15-8.02 (m, 1H), 7.40-7.36 (m,1H), 6.87-6.74 (m, 3H), 6.68 (d, J=7.8 Hz, 1H), 6.12 (d, J=16.6 Hz, 1H),6.04 (d, J=5.5 Hz, 1H), 5.69 (dd, J=10.5, 2.0 Hz, 1H), 4.50-4.21 (m,1H), 4.08-3.99 (m, 1H), 3.79 (s, 1H), 3.17-2.96 (m, 1H), 2.93 (s, 6H),2.82-2.61 (m, 1H), 1.96-1.94 (m, 1H), 1.84-1.58 (m, 2H), 1.45 (brs, 1H).

Example 944:N-(1-(2-Cyanoacetyl)piperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions to Example181, and using5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 865) in place of(R)-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 860) to give a white solid. MS (ESI): mass calcd. forC₃₀H₂₆N₆O₄S, 566.6; m/z found, 567.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 8.26 (d, J=7.3 Hz, 1H), 8.14 (d, J=5.2 Hz, 1H), 7.43-7.40 (m, 2H),7.25-7.23 (m, 1H), 7.18-7.14 (m, 1H), 7.10-7.03 (m, 3H), 6.94-6.91 (m,1H), 5.76 (d, J=4.9 Hz, 1H), 4.13-4.08 (m, 2H), 3.85-3.79 (m, 1H), 3.58(s, 2H), 3.18-3.08 (m, 2H), 2.02 (s, 3H), 1.83-1.76 (m, 2H), 1.47-1.34(m, 2H).

Example 945:(S)—N-(1-Benzylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(S)-4-oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 934) was dissolved in DCM (30 mL), followed by the addition ofNaBH(AcO)₃ and benzaldehyde. The reaction mixture was stirred at roomtemperature under N₂ overnight. The mixture was washed with sat Na₂CO₃solution and concentrated, purified by flash column chromatographyeluting with water (0.5% HCOOH)/MeOH to yield the title product as awhite solid. MS (ESI): mass calcd. for C₃₂H₂₇N₅O₃S, 561.7; m/z found,562.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.28 (d, J=5.1 Hz, 1H), 8.22(d, J=6.7 Hz, 1H), 8.13 (s, 1H), 7.53-7.38 (m, 4H), 7.36-7.26 (m, 4H),7.25-7.05 (m, 6H), 6.03 (d, J=5.3 Hz, 1H), 4.47-4.26 (m, 1H), 3.60 (s,2H), 2.83-2.75 (m, 1H), 2.68-2.57 (m, 1H), 2.55-2.48 (m, 1H), 2.46-2.37(m, 1H), 2.20-2.05 (m, 1H), 1.90-1.70 (m, 1H).

Example 946:(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepG-I in Example 1, using5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 55) and tert-butyl(3S)-3-aminopiperidine-1-carboxylate in place of5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylicacid (Intermediate 27) and tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G and using (E)-2-cyano-3-cyclopropylprop-2-enoic acid(Intermediate 17), DIEA, HATU, and DMF at room temperature instead ofprop-2-enoyl chloride, triethylamine an DCM in step I to yield a whitesolid. MS (ESI): mass calcd. for C₂₉H₂₈N₆O₄S, 556.6; m/z found, 557.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.28 (s, 1H), 8.28 (d, J=5.3 Hz,1H), 8.16-8.04 (m, 1H), 7.29-7.20 (m, 1H), 7.04-6.95 (m, 1H), 6.95-6.86(m, 1H), 6.68-6.46 (m, 1H), 5.88-5.84 (m, 1H), 4.11-4.00 (m, 1H),3.88-3.69 (m, 5H), 3.18-3.09 (m, 1H), 3.02-2.86 (m, 1H), 2.03 (s, 3H),1.94-1.83 (m, 2H), 1.82-1.73 (m, 1H), 1.70-1.59 (m, 1H), 1.53-1.41 (m,1H), 1.17-1.08 (m, 2H), 1.03-0.90 (br, 1H), 0.88-0.78 (br, 1H).

Example 947:5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using conditions analogous to Example921, using prop-2-ynoic acid in place of hydroxypropanoic acid to yielda white solid. MS (ESI): mass calcd. for C₃₀H₂₉N₅O₄S, 555.7; m/z found,556.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.28 (d, J=5.4 Hz, 1H), 7.69(d, J=7.4 Hz, 1H), 7.44-7.40 (m, 2H), 7.35 (d, J=8.6 Hz, 1H), 7.20-7.16(m, 1H), 7.11-7.06 (m, 3H), 6.97-6.94 (m, 1H), 5.93 (d, J=5.4 Hz, 1H),4.12-4.00 (m, 2H), 3.83-3.80 (m, 1H), 3.19-3.16 (m, 2H), 2.06 (s, 3H),2.03-1.99 (m, 2H), 1.80-1.77 (m, 2H), 1.37-1.31 (m, 2H), 0.97 (t, J=7.6Hz, 3H). Missing 1 proton signal.

Example 948:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-aminophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-nitrophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-I in Example 1, and using 4-nitroaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₃H₂₀N₆O₅S, 492.51; m/z found, 493.1[M+H]⁺.

Step B:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-aminophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)—N-(1-acryloylpiperidin-3-yl)-5-(4-nitrophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(200 mg, 0.406 mmol) in MeOH (10 mL) in a 25 mL round bottom flask wereadded a saturated solution NH₄Cl (10 mL) and Zn dust (0.500 g, 7.64mmol). The reaction mixture was stirred rt overnight, filtered, andconcentrated to dryness. The residue was purified by preparative HPLC(Gemini-C18, 150×21.2 mm, 5 μm, mobile phase A: H₂O (0.1% TFA (aq.)),V/V; B: acetonitrile, B in A from 20% to 25%) to give the title compound(39.5 mg, 21.0% yield) as a yellow solid. MS (ESI): mass calcd. forC₂₃H₂₂N₆O₃S, 462.5; m/z found, 463.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 10.37 (d, J=10.1 Hz, 1H), 8.39 (d, J=5.6 Hz, 1H), 8.19 (s, 1H),7.57-7.51 (m, 4H), 6.87-6.74 (m, 1H), 6.12 (d, J=16.7 Hz, 1H), 6.07 (d,J=5.6 Hz, 1H), 5.70 (d, J=10.5 Hz, 1H), 4.50-4.20 (m, 1H), 4.12-3.96 (m,1H), 3.79 (brs, 1H), 3.16-2.96 (m, 1H), 2.83-2.62 (m, 1H), 1.96-1.93 (m,1H), 1.85-1.61 (m, 2H), 1.44 (brs, 1H).

Example 949:(R)-5-(4-(Dimethylamino)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 4-nitroaniline and K₃PO₄ in place of2-methyl-4-phenoxyaniline and Cs₂CO₃ in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G as a white solid. MS (ESI): mass calcd. for C₂₂H₂₄N₆O₂S, 436.5;m/z found, 437.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.31 (d, J=6.9 Hz,1H), 8.26 (d, J=5.5 Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 7.16 (d, J=8.9 Hz,2H), 6.85 (d, J=9.1 Hz, 2H), 5.98 (d, J=5.5 Hz, 1H), 4.09 (s, 1H),3.28-3.25 (m, 1H), 3.14-3.11 (m, 1H), 2.98 (s, 6H), 2.80-2.70 (m, 2H),1.96-1.81 (m, 2H), 1.68-1.55 (m, 2H).

Example 950:(R)-4-Oxo-N-(piperidin-3-yl)-5-(m-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using m-toluidine in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₁H₂₁N₅O₂S, 407.5; m/z found, 408.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.56 (s, 1H), 8.27 (s, 1H), 8.16(s, 1H), 7.47-7.43 (m, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.15-7.12 (m, 2H),5.84 (s, 1H), 4.04 (s, 1H), 3.25-3.22 (m, 1H), 3.09-3.05 (m, 1H), 2.73(s, 2H), 2.38 (s, 3H), 1.95-1.92 (m, 1H), 1.85-1.82 (m, 1H), 1.67-1.50(m, 2H).

Example 951:(R)-5-(4-Chlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 4-chloroaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate and DIPEA in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate and triethylamine instep G. MS (ESI): mass calcd. for C₂₀H₁₈ClN₅O₂S, 427.9; m/z found, 428.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.32 (s, 1H), 9.37 (s, 1H), 9.18(s, 1H), 8.38-8.36 (m, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.6 Hz,2H), 6.11 (d, J=5.6 Hz, 1H), 4.28-4.15 (m, 1H), 3.31-3.29 (m, 1H),3.20-3.17 (m, 1H), 2.94-2.81 (m, 2H), 1.92-1.89 (m, 2H), 1.82-1.57 (m,2H).

Example 952:(R)-4-Oxo-N-(piperidin-3-yl)-5-(p-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using p-toluidine in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₁H₂₁N₅O₂S, 407.5; m/z found, 407.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.56 (s, 1H), 8.27 (s, 1H),8.19-8.15 (m, 1H), 7.59-7.56 (m, 2H), 7.51-7.47 (m, 1H), 7.36 (d, J=7.5Hz, 2H), 5.85-5.82 (m, 1H), 4.06 (s, 1H), 3.27-3.25 (m, 1H), 3.10-3.07(m, 1H), 2.75 (s, 2H), 1.95-1.93 (m, 1H), 1.86-1.83 (m, 1H), 1.66-1.57(m, 2H).

Example 953:(R)-5-(4-Fluorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 4-fluoroaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₀H₁₈FN₅O₂S, 411.5; m/z found, 411.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.56 (s, 1H), 8.30 (s, 1H),8.21-8.19 (m, 1H), 7.42-7.40 (m, 4H), 5.91-5.88 (m, 1H), 4.09 (s, 1H),3.28-3.25 (m, 1H), 3.12-3.09 (m, 1H), 2.79 (s, 2H), 1.98-1.81 (m, 2H),1.71-1.51 (m, 2H).

Example 954:(R)-5-(4-(tert-Butyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 4-(tert-butyl)aniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G and. MS (ESI): mass calcd. for C₂₄H₂₇N₅O₂S, 449.6; m/z found,450.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.21 (s, 1H), 9.15 (brs,1H), 8.99 (brs, 1H), 8.35 (d, J=5.6 Hz, 1H), 8.27 (d, J=7.5 Hz, 1H),7.62 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 6.01 (d, J=5.5 Hz, 1H),4.25-4.17 (m, 1H), 3.32-3.30 (m, 1H), 3.21-3.18 (m, 1H), 2.94-2.76 (m,2H), 1.97-1.85 (m, 2H), 1.78-1.58 (m, 2H), 1.36 (s, 9H).

Example 955:(R)-5-(4-Isopropoxy-3-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A: (R)-tert-Butyl3-(3-amino-4-((4-isopropoxy-3-methylphenyl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate

To a microwave vial containing a stir bar were added2-chloro-4-iodonicotinonitrile (1441 mg, 5.449 mmol),4-isopropoxy-3-methylaniline (907 mg, 5.49 mmol), DPEPhos (144 mg, 0.268mmol), Pd(OAc)₂ (58.0 mg, 0.258 mmol), and Cs₂CO₃ (1775 mg, 5.448 mmol).To the vial was added with dioxane (10 mL) via syringe and the mixturewas degassed under a vacuum for 1 minute, then vented to nitrogen. Thereaction was heated in the microwave at 150° C. for 30 minutes. Thereaction was cooled to room temperature, treated with (R)-tert-butyl3-(2-mercaptoacetamido)piperidine-1-carboxylate (Intermediate 22) (0.49M in dioxane, 10 mL, 4.9 mmol) via syringe, evacuated and flushed withnitrogen, and stirred at 150° C. for 20 min. The reaction was thencooled to room temperature. The reaction mixture was treated with solidCDI (2230 mg, 13.75 mmol) in one portion under air, resealed, evacuatedand flushed with nitrogen, and stirred at 150° C. for 20 min. The CDIreaction did not go, so the intermediate was purified. The reaction wasthen diluted with EtOAc (100 mL) and saturated aqueous sodiumbicarbonate (100 mL) and separated. The aqueous layer was extractedagain with EtOAc (100 mL), and the combined organics were dried overanhydrous MgSO₄, concentrated to dryness, and purified by flash columnchromatography to yield the title compound (558 mg, 19.0% yield). MS(ESI): mass calcd. for C₂₈H₃₇N₅O₄S, 539.70; m/z found, 540.2 [M+H]⁺.

Step B: (R)-tert-Butyl3-(5-(4-isopropoxy-3-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate

(R)-tert-Butyl3-(3-amino-4-((4-isopropoxy-3-methylphenyl)amino)thieno[2,3-b]pyridine-2-carboxamido)piperidine-1-carboxylate(558 mg, 1.03 mmol) was added to a 25 mL microwave vessel (Biotage) andtreated with Cs₂CO₃ (589 mg, 1.81 mmol) and CDI (360 mg, 2.22 mmol). Themixture was suspended in dioxane (10 mL), capped, and heated at 150° C.for 20 minutes. The reaction mixture was treated with DCM (20 mL),filtered, and concentrated to dryness. The residue was purified by flashcolumn chromatography to yield the title compound (478.1 mg, 81.74%yield) as a yellow oil. MS (ESI): mass calcd. for C₂₉H₃₅N₅O₅S, 565.69;m/z found, 566.1 [M+H]⁺.

Step C:(R)-5-(4-Isopropoxy-3-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

A solution of (R)-tert-butyl3-(5-(4-isopropoxy-3-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate(478.1 mg, 0.8450 mmol) in dioxane (4 mL) was treated with 4 M HCl indioxane (10 mL, 40 mmol). After 30 min at room temperature, a gummyprecipitate has settled on the bottom of the vial. The dioxane waspoured off, and the precipitate was treated with 20 mL saturated aqueoussodium bicarbonate, extracted DCM (2×50 mL), dried over anhydrous MgSO₄,concentrated to dryness. The residue was purified by flash columnchromatography, the pooled fractions were concentrated to dryness, takenup in DCM (2 mL), and were precipitated with 10 mL hexanes to give awhite precipitate. The precipitate was collected by filtration and driedunder a vacuum to give an off white solid. One fraction (63 mg) wassubjected to purification by reverse phase acidic HPLC to give the titlecompound (38.4 mg, 9.76% yield). MS (ESI): mass calcd. for C₂₄H₂₇N₅O₃S,465.6; m/z found, 466.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.55-8.40(d, J=7.6 Hz, 1H), 8.17-8.09 (d, J=5.5 Hz, 1H), 7.12-7.00 (s, 3H),5.90-5.81 (d, J=5.5 Hz, 1H), 4.70-4.59 (m, 1H), 4.25-3.37 (m, 3H),3.22-3.13 (m, 1H), 3.06-2.96 (d, J=12.1 Hz, 1H), 2.72-2.58 (m, 2H), 2.16(s, 3H), 1.98-1.86 (m, 1H), 1.84-1.70 (m, 1H), 1.64-1.45 (m, 2H),1.39-1.25 (d, J=5.9 Hz, 6H).

Example 956:(R)-5-(4-Aminophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(4-Nitrophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsC-H in Example 1, and using 4-nitroaniline in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G. MS (ESI): mass calcd. for C₂₀H₁₈N₆O₄S, 438.46; m/z found, 439.1[M+H]⁺.

Step B:(R)-5-(4-Aminophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)-5-(4-nitrophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(100 mg, 0.228 mmol) in MeOH (10 mL) was added 10% Pd/C (30 mg). Thereaction was stirred under a H₂ atmosphere at rt overnight. The Pd/C wasfiltered off and the filtrate was concentrated to dryness and waspurified by preparative HPLC (Gemini-C18, 150×21.2 mm, 5 μm, mobilephase A: H₂O (0.1% TFA (aq.)), V/V; B: acetonitrile, B in A from 20% to25%) to give the title compound (11.1 mg, 12.0% yield) as yellow solid.MS (ESI): mass calcd. for C₂₀H₂₀N₆O₂S, 408.5; m/z found, 409.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆): δ 10.20 (s, 1H), 9.12 (s, 1H), 8.98 (s, 1H),8.36 (d, J=5.5 Hz, 1H), 8.29 (d, J=5.6 Hz, 1H), 7.38 (s, 2H), 7.26 (s,2H), 6.06 (d, J=5.5 Hz, 1H), 4.20 (brs, 1H), 3.33-3.30 (m, 1H),3.22-3.19 (m, 1H), 2.94-2.77 (m, 2H), 1.92 (brs, 2H), 1.78-1.60 (m, 2H).

Example 957:(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-3-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using a method analogous to Example 75,using (EZ)-2-Chloro-3-cyclopropyl-prop-2-enoic acid (Intermediate 39)and(S)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 912) to yield a white solid. MS (ESI): mass calcd. forC₃₄H₃₀N₆O₄S, 618.7; m/z found, 619.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 10.22 (s, 1H), 8.37 (d, J=5.4 Hz, 1H), 8.16 (d, J=7.1 Hz, 1H),7.48-7.37 (m, 3H), 7.30-7.23 (m, 1H), 7.16-7.06 (m, 2H), 7.03-6.97 (m,2H), 6.63-6.57 (m, 1H), 6.03 (d, J=5.4 Hz, 1H), 4.18-3.80 (m, 3H),3.14-2.73 (m, 2H), 1.99 (s, 3H), 1.95-1.67 (m, 4H), 1.56-1.45 (m, 1H),1.20-1.11 (m, 2H), 1.02-0.83 (m, 2H).

Example 958:(R)-5-(*S)-(6-Isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-H (including Chiral Resolution Method A after step F to obtain the *Satropisomer) in Example 1, and using 2-fluoro-4-methyl-5-nitropyridineand 2-propanol in place of 5-fluoro-2-nitrotoluene and phenol in step A,and using Pd/C and MeOH in place of Fe, EtOH/H₂O, and NH₄Cl in step B,and using 6-isopropoxy-4-methylpyridin-3-amine in place of2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopyrrolidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G and using TFA in place of HCl in step H. MS (ESI): mass calcd.for C₂₂H₂₄N₆O₃S, 452.5; m/z found, 453.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃): δ 8.30 (d, J=5.5 Hz, 1H), 8.01 (s, 1H), 7.62 (s, 1H), 6.71 (d,J=0.8 Hz, 1H), 6.01 (d, J=5.5 Hz, 1H), 4.75 (s, 1H), 3.55-3.36 (m, 6H),3.26 (ddd, J=11.4, 8.6, 6.4 Hz, 1H), 2.42-2.31 (m, 1H), 2.20-2.08 (m,4H), 1.36 (dd, J=14.5, 6.1 Hz, 6H).

Example 959:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepI in Example 1, using(R)-5-(*S)-(6-Isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 958), acrylic anhydride and DIPEA in place ofN-((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,prop-2-enoyl chloride and triethylamine. MS (ESI): mass calcd. forC₂₅H₂₆N₆O₄S, 506.6; m/z found, 507.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): δ8.34 (t, J=5.6 Hz, 1H), 8.01 (d, J=4.6 Hz, 1H), 6.72 (s, 1H), 6.49-6.31(m, 2H), 6.04 (dd, J=8.0, 5.4 Hz, 1H), 5.70 (ddd, J=16.2, 9.1, 3.2 Hz,1H), 5.38-5.26 (m, 1H), 4.80-4.65 (m, 1H), 4.12 (q, J=7.1 Hz, 1H),3.85-3.61 (m, 3H), 2.39-2.19 (m, 2H), 2.16-1.99 (m, 5H), 1.45-1.28 (m,6H).

Example 960:(R,E)-N-(1-(2-Cyano-3-(1-methylcyclobutyl)acryloyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

Step A:(R)-5-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared using analogous conditions described inMethod 1, steps A-H in Example 1, and using6-chloro-2-methyl-3-nitropyridine in place of 5-fluoro-2-nitrotoluene instep A and using Pd/C and MeOH in place of Fe, EtOH/H₂O, and NH₄Cl instep B, and using 2-methyl-6-phenoxypyridin-3-amine (Intermediate 49) inplace of 2-methyl-4-phenoxyaniline in step C, and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoro-piperidine-1-carboxylate in step G to yield thetitle compound. MS (ESI): mass calcd. for C₂₆H₂₄N₆O₃S, 500.57; m/zfound, 501.1 [M+H]⁺.

Step B:(R,E)-N-(1-(2-Cyano-3-(1-methylcyclobutyl)acryloyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a round bottom flask were added(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 77, 200 mg, 0.352 mmol), 3-methyloxetane-3-carbaldehyde(106 mg, 1.06 mmol), piperidine (0.3 mL), AcOH (0.1 mL), 4A molecularsieves (500 mg), and dioxane (5 mL) and was stirred at reflux for 1 h.The mixture was filtered and the filtrate was concentrated to dryness.The residue was purified by normal phase flash column chromatography(SiO₂) to give the title compound (165 mg, 72.1% yield) as light yellowsolid. MS (ESI): mass calcd. for C₃₄H₃₁N₇O₅S, 649.72; m/z found, 650.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.25 (s, 1H), 8.36-8.32 (m, 1H),8.24-8.07 (m, 1H), 7.91-7.82 (m, 1H), 7.48-7.40 (m, 2H), 7.35-7.31 (m,1H), 7.27-7.18 (m, 3H), 7.02-6.97 (m, 1H), 6.11-6.06 (m, 1H), 4.88-4.52(m, 2H), 4.45-4.01 (m, 3H), 3.97-3.79 (m, 2H), 3.19-2.98 (m, 1H),2.96-2.61 (m, 1H), 2.15-2.09 (m, 3H), 2.01-1.89 (m, 1H), 1.88-1.76 (m,1H), 1.74-1.48 (m, 5H).

Example 961:N¹-((E)-4-((R)-3-(1-(2-Methyl-6-phenoxypyridin-3-yl)-2-oxo-1,2,3,5-tetrahydrocyclopenta[de]quinazoline-4-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)-N⁵-(15-oxo-19-((3aR,4R,6aS)-2-oxooctahydrocyclopenta[d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)glutaramide

Step A:5,21-Dioxo-25-((3aR,4R,6aS)-2-oxooctahydrocyclopenta[d]imidazol-4-yl)-10,13,16-trioxa-6,20-diazapentacosan-1-oicacid

The title compound was prepared using analogous conditions described inExample 237, steps A-E as a white solid.

Step B: (R,E)-tert-Butyl(4-(3-(5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate

The title compound was prepared in a manner analogous to Method 1, stepsA-I in Example 1, and using 6-chloro-2-methyl-3-nitropyridine in placeof methyl (2R,4S)-4-hydroxypyrrolidine-2-carboxylate in step A, andusing Pd/C and MeOH in place of Fe, EtOH/H₂O, and NH₄Cl in step B, andusing 2-methyl-6-phenoxypyridin-3-amine (Intermediate 49) in place of2-methyl-4-phenoxyaniline in step C, and using and using (R)-tert-butyl3-aminopiperidine-1-carboxylate in place of tert-butyl(3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate (Intermediate 1) instep G, and using (E)-4-((tert-butoxycarbonyl)amino)but-2-enoic acid,DMF, and HATU in place of prop-2-enoyl chloride and DCM in step I.

Step C:N¹-((E)-4-((R)-3-(1-(2-Methyl-6-phenoxypyridin-3-yl)-2-oxo-1,2,3,5-tetrahydrocyclopenta[de]quinazoline-4-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)-N⁵-(15-oxo-19-((3aR,4R,6aS)-2-oxooctahydrocyclopenta[d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)glutaramide

A solution of (R,E)-tert-butyl(4-(3-(5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)carbamate(900 mg, 1.32 mmol) in 4.0 M HCl in methanol (20 mL) was stirred at roomtemperature for 1 hour. The reaction was concentrated to dryness to givede-Boc product. A solution of5,21-dioxo-25-((3aR,4R,6aS)-2-oxooctahydrocyclopenta[d]imidazol-4-yl)-10,13,16-trioxa-6,20-diazapentacosan-1-oicacid (738 mg, 1.32 mmol), triethylamine (266 mg, 2.63 mmol), and HATU(600 mg, 1.58 mmol) in DMF (10 mL) was stirred at room temperature for15 minutes to give the activated-ester solution. The de-Boc product wasdissolved in DMF (10 mL) and triethylamine (266 mg, 2.63 mmol) and theactivated-ester solution was added to it. The mixture was stirred atroom temperature for 10 minutes and TLC showed the reaction had gone tocompletion. The mixture was purified by normal phase flash columnchromatography (SiO₂) to give the title compound (1.1 g, 99% yield) as alight yellow solid. MS (ESI): mass calcd. for C₅₅H₇₁D₅N₁₁O₁₁S₂, 1126.35;m/z found, 1126.5 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.40-8.32 (m, 1H),7.90-7.76 (m, 1H), 7.50-7.41 (m, 2H), 7.27-7.22 (m, 1H), 7.22-7.15 (m,2H), 6.95-6.87 (m, 1H), 6.76-6.64 (m, 1H), 6.59-6.50 (m, 1H), 6.20-6.12(m, 1H), 4.52-4.42 (m, 1H), 4.33-4.07 (m, 2H), 4.03-3.87 (m, 3H),3.67-3.43 (m, 12H), 3.28-3.12 (m, 6H), 3.05-2.83 (m, 2H), 2.74-2.63 (m,1H), 2.32-2.24 (m, 5H), 2.24-2.13 (m, 4H), 2.12-1.99 (m, 1H), 1.97-1.82(m, 3H), 1.80-1.50 (m, 10H), 1.48-1.35 (m, 2H).

Example 962:(R,E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

To a solution of(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 77) (500 mg, 0.881 mmol), 2-ethoxy-2-methylpropanal (205mg, 1.76 mmol), and acetic acid (100 μL) in dioxane (15 mL) was addedpiperidine (300 μL) and heated at refluxed for 1 h. The reaction wasconcentrated to dryness and purified by normal phase flash columnchromatography (SiO₂) to give the title compound (86 mg, 14% yield) andas a pale yellow solid. MS (ESI): mass calcd. for C₃₅H₃₅N₇O₅S, 665.76;m/z found, 666.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 8.36-8.26 (m, 1H),7.85-7.74 (m, 1H), 7.48-7.38 (m, 2H), 7.28-7.14 (m, 3H), 6.93-6.83 (m,2H), 6.15-6.06 (m, 1H), 4.52-3.81 (mz, 3H), 3.54-3.43 (m, 2H), 3.28-2.74(m, 2H), 2.28-2.18 (m, 3H), 2.10-2.01 (m, 1H), 1.96-1.85 (m, 1H),1.81-1.57 (m, 2H), 1.47-1.32 (m, 6H), 1.27-1.12 (m, 3H).

Example 963:(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

solution of(R)—N-(1-(2-cyanoacetyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Intermediate 77) (500 mg, 0.881 mmol), cyclopropanecarbaldehyde (617mg, 8.81 mmol), acetic acid (0.1 mL), piperidine (0.3 mL), and 4Amolecular sieves (500 mg) in dioxane (8 mL) was purged with N₂, and thenwas stirred at 105° C. for 1 h. The solid was filtrated off and theliquid was purified by normal phase flash column chromatography (SiO₂)to give the title compound (190 mg, 34.8% yield) as a grey solid. MS(ESI): mass calcd. for C₃₃H₂₉N₇O₄S, 619.69; m/z found, 620.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): δ 9.51 (s, 1H), 8.38 (d, J=5.5 Hz, 1H), 7.59-7.48(m, 1H), 7.46-7.39 (m, 2H), 7.26-7.18 (m, 3H), 6.83-6.80 (m, 1H),6.79-6.62 (m, 1H), 6.05 (d, J=5.5 Hz, 1H), 4.24-4.09 (m, 1H), 4.09-3.29(m, 4H), 2.30-2.25 (m, 3H), 2.13-1.87 (m, 3H), 1.84-1.68 (m, 2H),1.28-1.23 (m, 2H), 1.02-0.84 (m, 2H).

Example 29:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(2-meth-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 781) was resolved by chiral SFC (Stationary phase: CHIRALCELOJ-H, 5 μm, 250×20 mm, Mobile phase: 80% CO₂, 20% MeOH) to yield the *Ratropisomer, followed by Method 1, step I in Example 1, to yield thetitle compound. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₄S, 540.6; m/z found,541.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.53 (d, J=24.1 Hz, 1H), 8.37(t, J=5.4 Hz, 1H), 8.25 (dd, J=4.9, 2.1 Hz, 1H), 7.75 (tt, J=8.3, 1.5Hz, 1H), 7.26-6.92 (m, 5H), 6.51-6.33 (m, 2H), 6.10 (dd, J=7.1, 4.6 Hz,1H), 5.83-5.59 (m, 1H), 5.30 (d, J=2.8 Hz, 1H), 4.73 (dd, J=14.9, 8.7Hz, 1H), 4.06-3.51 (m, 4H), 2.45-1.72 (m, 5H).

Example 30:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-meth-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 781) was resolved by chiral SFC (Stationary phase: CHIRALCELOJ-H, 5 μm, 250×20 mm, Mobile phase: 80% CO₂, 20% MeOH) to yield the *Satropisomer, followed by Method 1, step I in Example 1, to yield thetitle compound. MS (ESI): mass calcd. for C₂₈H₂₄N₆O₄S, 540.6; m/z found,541.2 [M+H]⁺. 1H NMR (400 MHz, Chloroform-d) δ 9.52 (d, J=24.8 Hz, 1H),8.45-8.32 (m, 1H), 8.32-8.20 (m, 1H), 7.84-7.68 (m, 1H), 7.22-6.94 (m,4H), 6.54-6.34 (m, 2H), 6.17-6.00 (m, 1H), 5.81-5.65 (m, 1H), 5.36-5.25(m, 1H), 4.79-4.62 (m, 1H), 4.02-3.51 (m, 4H), 2.44-1.99 (m, 5H),1.83-1.48 (m, 1H).

Example 31:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 778) was resolved by chiral SFC (Stationary phase: CHIRALCELOD-H, 5 μm, 250×30 mm, Mobile phase: 45% CO₂, 55% MeOH) to yield the *Ratropisomer, followed by Method 1, step I in Example 1, to yield thetitle compound. MS (ESI): mass calcd. for C₂₉H₂₆N₆O₄S, 554.6; m/z found,555.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.47 (s, 1H), 8.51-8.02 (m,2H), 7.93-7.68 (m, 1H), 7.26-6.93 (m, 4H), 6.71-6.16 (m, 2H), 6.20-5.45(m, 3H), 4.23-3.29 (m, 5H), 2.17 (s, 3H), 2.10-1.55 (m, 5H).

Example 32:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 778) was resolved by chiral SFC (Stationary phase: CHIRALCELOD-H, 5 μm, 250×30 mm, Mobile phase: 45% CO₂, 55% MeOH) to yield the *Satropisomer, followed by Method 1, step I in Example 1, to yield thetitle compound. MS (ESI): mass calcd. for C₂₉H₂₆N₆O₄S, 554.6; m/z found,555.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.46 (s, 1H), 8.41-8.18 (m,2H), 7.86-7.67 (m, 1H), 7.26-6.81 (m, 5H), 6.71-5.45 (m, 4H), 4.28-3.23(m, 5H), 2.35-1.46 (m, 8H).

Example 33:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 773) was resolved by chiral SFC (Stationary phase: CHIRALCELOD-H, 5 μm, 250×30 mm, Mobile phase: 45% CO₂, 55% MeOH) to yield the *Ratropisomer, followed by Method 1, step I in Example 1, to yield thetitle compound. MS (ESI): mass calcd. for C₃₀H₂₈N₆O₄S, 568.7; m/z found,569.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.48 (s, 1H), 8.46-8.25 (m,2H), 7.42-7.31 (m, 1H), 7.25-7.13 (m, 2H), 7.05-6.81 (m, 2H), 6.76-6.21(m, 3H), 6.03-5.97 (m, 1H), 5.73 (d, J=12.0 Hz, 1H), 4.26-3.21 (m, 5H),2.54 (s, 3H), 2.16-1.64 (m, 7H).

Example 34:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 773) was resolved by chiral SFC (Stationary phase: CHIRALCELOD-H, 5 μm, 250×30 mm, Mobile phase: 45% CO₂, 55% MeOH) to yield the *Satropisomer, followed by Method 1, step I in Example 1, to yield thetitle compound. MS (ESI): mass calcd. for C₃₀H₂₈N₆O₄S, 568.7; m/z found,569.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.49 (s, 1H), 8.53-8.26 (m,2H), 7.42-7.25 (m, 1H), 7.22-7.08 (m, 2H), 7.03-6.86 (m, 2H), 6.72-6.23(m, 3H), 6.09-5.69 (m, 2H), 4.27-3.24 (m, 5H), 2.54 (s, 3H), 2.22-1.62(m, 7H).

Example 35:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 784) was resolved by chiral SFC (Stationary phase: CHIRALCELOJ-H, 5 μm, 250×20 mm, Mobile phase: 75% CO₂, 25% MeOH) to yield the *Ratropisomer, followed by Method 1, step I in Example 1, to yield thetitle compound. MS (ESI): mass calcd. for C₂₈H₂₅N₇O₄S, 555.6; m/z found,556.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.49 (s, 1H), 9.09-8.92 (m,1H), 8.48-8.29 (m, 1H), 7.70-7.49 (m, 1H), 7.38-7.22 (m, 5H), 6.76-5.49(m, 3H), 4.26-3.22 (m, 5H), 2.20 (s, 3H), 2.16-1.64 (m, 5H).

Example 36:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-meth-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide(Example 784) was resolved by chiral SFC (Stationary phase: CHIRALCELOJ-H, 5 μm, 250×20 mm, Mobile phase: 75% CO₂, 25% MeOH) to yield the *Satropisomer, followed by Method 1, step I in Example 1, to yield thetitle compound. MS (ESI): mass calcd. for C₂₈H₂₅N₇O₄S, 555.6; m/z found,556.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.49 (s, 1H), 9.09-8.92 (m,1H), 8.48-8.29 (m, 1H), 7.70-7.49 (m, 1H), 7.38-7.22 (m, 5H), 6.76-5.49(m, 3H), 4.26-3.22 (m, 5H), 2.20 (s, 3H), 2.16-1.64 (m, 5H).

Example 972:(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-(pyridazin-3-yloxy)pyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA, C-G, and using 3,6-dichloropyridazine and 6-aminopyridin-3-ol inplace of 5-fluoro-2-nitrotoluene and phenol in step A, and no step B,and using 5-(pyridazin-3-yloxy)pyridin-2-amine in place of2-methyl-4-phenoxyaniline in step C, and using(R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₆H₂₂N₈O₄S,542.6; m/z found, 543.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 9.02-8.94 (m,1H), 8.62 (s, 1H), 8.27 (d, J=5.4 Hz, 1H), 8.04-7.95 (m, 1H), 7.83-7.70(m, 2H), 7.60-7.51 (m, 1H), 6.88-6.68 (m, 1H), 6.36-6.26 (m, 1H),6.23-6.11 (m, 1H), 5.74-5.63 (m, 1H), 4.57-4.27 (m, 1H), 4.24-3.85 (m,2H), 3.17-3.04 (m, 1H), 2.89-2.76 (m, 1H), 2.07-1.96 (m, 1H), 1.87-1.78(m, 1H), 1.75-1.62 (m, 1H), 1.59-1.45 (m, 1H).

Example 973:(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-(pyridazin-3-yloxy)pyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA, C-G, and using 3,6-dichloropyridazine and 6-aminopyridin-3-ol inplace of 5-fluoro-2-nitrotoluene and phenol in step A, and no step B,and using 5-(pyridazin-3-yloxy)pyridin-2-amine in place of2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate 5) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₅H₂₀N₈O₄S,528.5; m/z found, 529.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 10.31 (s,1H), 9.07 (s, 1H), 8.64 (s, 1H), 8.42-8.30 (m, 2H), 8.10-8.02 (m, 1H),7.90-7.80 (m, 1H), 7.80-7.70 (m, 1H), 7.68-7.60 (m, 1H), 6.66-6.47 (m,1H), 6.24-6.06 (m, 2H), 5.70-5.60 (m, 1H), 4.57-4.38 (m, 1H), 3.93-3.48(m, 3H), 3.48-3.36 (m, 1H), 2.26-1.90 (m, 2H).

Example 974:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-6-(pyridazin-3-yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G, and using 3,6-dichloropyridazine and 5-aminopyridin-2-ol in placeof 5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C and MeOHin place of Fe, EtOH/H₂O, and NH₄Cl in step B, and using2-methyl-6-(pyridazin-3-yloxy)pyridin-3-amine in place of2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate 5) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate(Intermediate 1) in step G. MS (ESI): mass calcd. for C₂₆H₂₂N₈O₄S,542.6; m/z found, 543.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 9.11-9.03 (m,1H), 8.39-8.33 (m, 1H), 8.04-7.95 (m, 1H), 7.89-7.82 (m, 1H), 7.71-7.64(m, 1H), 7.33-7.26 (m, 1H), 6.69-6.53 (m, 1H), 6.33-6.22 (m, 2H),5.80-5.70 (m, 1H), 4.68-4.55 (m, 1H), 4.06-3.73 (m, 2H), 3.70-3.51 (m,2H), 2.37-2.10 (m, 5H).

Example 975:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-(pyridazin-3-yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G, and using 3,6-dichloropyridazine and 5-aminopyridin-2-ol in placeof 5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/C and MeOHin place of Fe, EtOH/H₂O, and NH₄Cl in step B, and using2-methyl-6-(pyridazin-3-yloxy)pyridin-3-amine in place of2-methyl-4-phenoxyaniline in step C, and using(R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate. MS(ESI): mass calcd. for C₂₇H₂₄N804S, 556.6; m/z found, 557.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 9.11-9.04 (m, 1H), 8.42-8.34 (m, 1H), 8.27-8.18(s, 1H), 8.03-7.95 (m, 1H), 7.89-7.82 (m, 1H), 7.70-7.62 (m, 1H),7.34-7.26 (m, 1H), 6.87-6.74 (m, 1H), 6.28-6.14 (m, 2H), 5.80-5.67 (m,1H), 4.63-4.26 (m, 1H), 4.22-3.89 (m, 2H), 3.25-3.09 (m, 1H), 2.99-2.82(m, 1H), 2.31-2.23 (m, 3H), 2.14-2.01 (m, 1H), 1.93-1.82 (m, 1H),1.78-1.67 (m, 1H), 1.66-1.53 (m, 1H).

Example 976:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-6-(pyridazin-3-yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G, and using 3,6-dichloropyridazine and 5-amino-4-methylpyridin-2-olin place of 5-fluoro-2-nitrotoluene and phenol in step A, and usingPd/C, DIPEA, and MeOH in place of Fe, EtOH/H₂O, and NH₄Cl in step B, andusing 4-methyl-6-(pyridazin-3-yloxy)pyridin-3-amine in place of2-methyl-4-phenoxyaniline in step C, and using(R)-1-(3-aminopiperidin-1-yl)prop-2-en-1-one (Intermediate 15) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate. MS(ESI): mass calcd. for C₂₇H₂₄N₈O₄S, 556.6; m/z found, 557.2 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.95-8.81 (m, 1H), 8.22-8.13 (m, 1H), 8.06-7.99(m, 1H), 7.74-7.59 (m, 1H), 7.51-7.42 (m, 1H), 7.25-7.15 (m, 1H),6.70-6.51 (m, 1H), 6.11-5.92 (m, 2H), 5.62-5.46 (m, 1H), 4.43-4.05 (m,1H), 4.05-3.69 (m, 2H), 3.08-2.90 (m, 1H), 2.84-2.61 (m, 1H), 2.15-2.05(m, 3H), 1.96-1.81 (m, 1H), 1.76-1.31 (m, 3H).

Example 977:(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-methyl-6-(pyridazin-3-yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide

The title compound was prepared in a manner analogous to Method 1, stepsA-G, and using 3,6-dichloropyridazine and 5-amino-4-methylpyridin-2-olin place of 5-fluoro-2-nitrotoluene and phenol in step A, and using Pd/Cand MeOH in place of Fe, EtOH/H₂O, and NH₄Cl in step B, and using4-methyl-6-(pyridazin-3-yloxy)pyridin-3-amine in place of2-methyl-4-phenoxyaniline in step C, and using1-[(3R)-3-aminopyrrolidin-1-yl]prop-2-en-1-one (Intermediate 5) in placeof tert-butyl (3R,5R)-3-amino-5-fluoropiperidine-1-carboxylate. MS(ESI): mass calcd. for C₂₆H₂₂N₈O₄S, 542.6; m/z found, 543.2 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD): δ 8.89 (d, J=1.3 Hz, 1H), 8.19 (d, J=5.6 Hz, 1H),8.04 (s, 1H), 7.72-7.61 (m, 1H), 7.48 (d, J=7.1 Hz, 1H), 7.21 (s, 1H),6.53-6.31 (m, 1H), 6.16-6.00 (m, 2H), 5.62-5.52 (m, 1H), 4.44 (s, 1H),3.90-3.26 (m, 4H), 2.24-2.04 (m, 4H), 2.02-1.84 (m, 1H).

BTK Kinase Lanthascreen Binding Assay:

A BTK kinase lanthascreen binding assay monitors compound binding tounphosphorylated-BTK kinase domain (UP-BTK), by competing with afluorescent labeled tracer. UP-BTK, consisting of the kinase domain ofnon-phosphorylated BTK protein (389-659aa), was produced in aBaculovirus/insect cell expression system. Into a 384-well plate, 2 ngof GST-tagged human BTK (389-659aa) was incubated with compound, 50 nMof Tracer 236 and 2 nM anti-GST antibody for 60 minutes using anoptimized Lanthascreen™ assay. After 60 minutes, plates were read at 340nM and 615/665 nM in an Infinite F500 (Tecan). Data were analyzed usingXlfit™ version 5.3 from ID Business Solutions (Guildford), MicrosoftExcel add-in. pIC₅₀ refers to the negative log of the IC₅₀ in molar.

TABLE 2 BTK_I_binding Ex # Compound Name pIC50 1N-((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(2-methyl-4- 7.7phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 2N-((3R,5S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(*S)-(2-methyl-4- 8.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 3N-((3R,5S)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(2-methyl-4- 7.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 4(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-fluoro-2-methyl-4- 7.7phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 5(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4- 8.1phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 6N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2-methyl-4- 7.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 7(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(3-fluoro-2-methyl-4- 7.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 8N-((3R,5R)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2-methyl-4- 7.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 9(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4- 8.1phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 10(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-fluoro-4-phenoxyphenyl)-4- 8.1oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 11(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 7.9oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 12(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2-chloro-4-phenoxyphenyl)-4- 7.7oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 13N-((3R,5S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2-methyl-4- 7.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 14N-((3R,5S)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2-methyl-4- 7.4phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 15(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-chloro-4-phenoxyphenyl)-4- 7.6oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 16(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-(benzofuran-7-yloxy)-2- 7.3methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 17(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(2,6-difluorophenoxy)-2- 7.7methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 18(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 8.2dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 19(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-(2-ethylphenoxy)-2- 7.2methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 20(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-fluoro-6-methyl-4- 7.4phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 21(R,E)-N-(1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3- 7.7yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 22(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(benzofuran-7-yloxy)-2- 7.4methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 23(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4- 7.5(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 24(R)-5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-N- 7.7(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 25(S,E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4- 7.5phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 26(R)-N-(1-(2-Chloroacryloyl)piperidin-3-yl)-5-(2-methyl-4- 7.3phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 27(R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4- 7.3phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 28N-((3S,4R)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(*S)-(2-methyl-4- 7.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 29(R,EZ)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3- 7.3yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 30(R,E)-N-(1-(4-Hydroxybut-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4- 7.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 31N-(4-Cyano-1,4-oxazepan-6-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 7.7oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 32(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-(cyclohexyloxy)-2- 7.3methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 33(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)- 7.54-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;34 N-((3S,4R)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(2-methyl-4- 7.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 35(R)-N-(1-Cyanopiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)- 7.54-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;36 N-((3S,4S)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(2-methyl-4- 7.7phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 37N-((3S,4R)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(2-methyl-4- 7.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 38(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4- 7.3(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 39(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(cyclohexyloxy)-2- 7.4methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 40(R,E)-N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3- 7.6yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 41(R,E)-N-(1-(2-Cyano-3-13C-cyclopropylacryloyl)piperidin-3-yl)-5- 7.3(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 42(R)-N-(1-(But-2-ynoyl)piperidin-3-yl)-5-(2-methyl-4- 7.0phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 43(R,E)-N-(1-(2-Cyano-4-methyl-4-morpholinopent-2-enoyl)piperidin- 7.23-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 44(S)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4- 7.4phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 45(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2-fluoro-6-methyl-4- 7.1phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 46(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(1- 7.9propioloylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 47(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5- 8.0(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 48(R)-N-(1-(2-Fluoroacryloyl)piperidin-3-yl)-5-(2-methyl-4- 6.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 49(R)-N-(1-(2-Fluoroacryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4- 7.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 50N-((3S,4S)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(2-methyl-4- 7.5phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 51(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-cyclopropoxy-2- 7.5methylphenyl)-4-oxo-4,5-dihydro-3 H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 52(R)-5-(4-(2,6-Difluorophenoxy)-2-methylphenyl)-N-(1- 7.0methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 54N-((3S,4S)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(2-methyl-4- 7.3phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 55(R)-N-(1-(But-2-ynoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4- 7.4phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 56(R)-N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-5-(*S)-(2- 7.4methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 57(R)-5-(4-(2-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin- 6.83-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 58N-((3S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(2-methyl-4- 7.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 59(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-methylpiperidin- 7.33-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 60(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propylpiperidin-3- 6.8yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 61(S)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro- 7.32H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 62(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-ethyl-2-methylphenyl)-4-oxo- 7.14,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 63(R,E)-N-(1-(2-Cyano-4-methyl-4-(tetrahydro-2H-pyran-4-yl)pent-2- 7.2enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 64(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-(2,6-difluorophenoxy)-2- 7.6methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 65(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((tetrahydro-2H- 6.6pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 66(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-ethoxy-2-methylphenyl)-4- 7.4oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 67(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3- 7.5yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 68(S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3- 7.7yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 69(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2,6-difluoro-4-phenoxyphenyl)- 7.74-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;70 (R)-5-(4-(Benzofuran-7-yloxy)-2-methylphenyl)-N-(1- 7.1methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 71(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro- 7.52H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 72(R)-N-(1-(3-Methoxypropanoyl)pyrrolidin-3-yl)-5-(2-methyl-4- 7.4phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 73(R)-5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-N-(1- 6.8methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 74(R)-N-(1-Ethylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo- 6.94,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 75(R)-N-(1-(3-Hydroxypropanoyl)piperidin-3-yl)-5-(2-methyl-4- 7.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 76(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(2- 6.8ethylphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 77(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2,3-dimethyl-4- 6.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 78(R)-N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-5-(2-methyl-4- 7.3phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 79(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 7.5fluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 80(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran- 7.83-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;81 (R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2,6-dimethyl-4- 6.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 82(S)-N-(1-acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4- 7.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 83(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4- 6.8(pentafluorothio)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 84(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1- 7.5propionylpyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 85 (R)-Tetrahydro-2H-pyran-3-yl5-(2-methyl-4-phenoxyphenyl)-4-oxo- 7.64,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate; 86(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2,4-dimethylphenyl)-4-oxo-4,5- 6.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 87(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4- 6.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 88(S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H- 7.6pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 89 (R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(3- 7.1methoxypropanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 90(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)- 7.54,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 91(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2- 7.3(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 92N-(1,6-Dimethylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 6.8oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 93(R)-N-(1-Isopropylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4- 7.1phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 94N-((3S,4R)-4-Fluoro-1-(3-methoxypropanoyl)pyrrolidin-3-yl)-5-(2- 7.6methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 95(R)-N-(1-(2-Methoxyacetyl)piperidin-3-yl)-5-(2-methyl-4- 7.4phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 96(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2 H- 7.8pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 97N-(1-Cyanoazepan-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5- 6.9dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 98(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)- 7.34,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 99(R)-N-(1-(3-Hydroxypropanoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4- 7.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 100(R,E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4- 7.1phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 101(R)-N-(1-Isopropylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 6.8oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 102(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4- 7.5isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 103N-(1,6-Dimethylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 6.7oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 104(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3- 7.7(methylsulfonyl)propanoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 105(R,E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(2-methyl-4- 6.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 106(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3- 7.3(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 107(R)-5-(2-Fluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5- 7.5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 108(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)- 7.54,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 109N-(1-Acryloylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo- 7.24,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 110(R)-N-(1-13C-Acryloylpiperidin-3-yl)-5-(4-methoxy-2- 6.8methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 111N-((R)-1-((R)-2-Amino-3-methoxypropanoyl)piperidin-3-yl)-5-(2- 7.2methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 112(R,E)-N-(1-(2-Cyano-4-methyl-4-morpholinopent-2-enoyl)piperidin- 6.93-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 113(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(3- 7.3(methylsulfonyl)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 114(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(2- 7.3hydroxyacetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 115(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(2- 7.4methoxyacetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 116(R,Z)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(2-methyl-4- 7.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 117(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4- 6.9oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 118(R)-N-(1-Isopropylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 6.9oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 119(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(4-ethyl-2-methylphenyl)-4- 6.6oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 120N-((R)-1-((S)-2-Amino-3-methoxypropanoyl)piperidin-3-yl)-5-(2- 7.1methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 121(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridazin-3- 6.7yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 122N-((R)-1-((S)-2-Hydroxy-3-methoxypropanoyl)piperidin-3-yl)-5-(2- 7.4methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 1235-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-4-yl)- 6.94,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 124(R)-N-(1-(2-Hydroxyacetyl)piperidin-3-yl)-5-(2-methyl-4- 7.4phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 1255-(2-Methyl-4-phenoxyphenyl)-N-((R)-1-((S)-1-methylpyrrolidine-3- 7.2carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 126(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)- 6.74-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;127 (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-7.3 4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 128 (R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(3- 7.2hydroxypropanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 129N-(4-Methyl-1,4-oxazepan-6-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 6.9oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 130(R)-N-(1-(3-(Dimethylamino)propanoyl)piperidin-3-yl)-5-(2-methyl- 7.14-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 1315-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-((R)-1-((S)-pyrrolidine-3- 7.5carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 132N-((3S,4R)-4-Fluoro-1-methylpyrrolidin-3-yl)-5-(2-methyl-4- 7.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 133(R)-5-(2-Chloro-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4- 7.0oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 134(R,Z)-N-(1-(2-Cyano-4-(dimethylamino)-4-methylpent-2- 7.1enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 135(R)-5-(2-Fluoro-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4- 7.2oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 136(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(oxetane-3- 7.1carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 137(R)-N-(1-Acryloylpyrrolidin-3-yl)-N-methyl-5-(2-methyl-4- 6.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 138N-((3R,5R)-5-Fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)- 7.04-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;139 N-((3S,4S)-4-Hydroxy-1-(3-methoxypropanoyl)pyrrolidin-3-yl)-5-(2-7.2 methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 140(R)-N-(1-(2-Cyano-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl- 6.74-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 141(R)-N-(1-Ethylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 6.8oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 142N-((R)-1-((S)-2,3-Dimethoxypropanoyl)piperidin-3-yl)-5-(2-methyl- 7.24-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 143N-((R)-1-((R)-2-Hydroxy-3-methoxypropanoyl)piperidin-3-yl)-5-(2- 7.3methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 144(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(2- 7.5(trifluoromethyl)acryloyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 1455-(2-Methyl-4-phenoxyphenyl)-N-((R)-1-((R)-1-methylpyrrolidine-3- 7.0carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 146(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3- 7.4(methylsulfonyl)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 147(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3- 7.4yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 148(R)-5-(2-Methyl-4-(o-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4- 6.9oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 149(R)-N-(1-Cyclopropylpyrrolidin-3-yl)-5-(2-methyl-4- 6.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 150(R,E)-N-(1-(2-Cyano-4-methyl-4-(piperidin-1-yl)pent-2- 6.9enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 151(R)-N-(1-(2-Aminoacetyl)piperidin-3-yl)-5-(2-methyl-4- 7.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 152(R,E)-N-(1-(2-Cyano-4-(cyclopropylamino)-4-methylpent-2- 7.3enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 1535-(2-Methyl-4-phenoxyphenyl)-N-((6S)-6-methylpiperidin-3-yl)-4- 6.8oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 154N-((3S,4R)-4-Fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)- 7.24-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;155 N-((3R)-1-(3-Methoxybutanoyl)piperidin-3-yl)-5-(2-methyl-4- 7.0phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 156N-((R)-1-((S)-3-Methoxy-2-methylpropanoyl)piperidin-3-yl)-5-(2- 7.1methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 157(R)-5-(4-(2-Ethoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin- 6.63-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 158N-((3R)-1-(3-Methoxy-2-methylpropanoyl)piperidin-3-yl)-5-(2- 7.1methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 159(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5- 7.1dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 160N-((3R,5R)-5-Fluoro-1-methylpiperidin-3-yl)-5-(2-methyl-4- 6.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 161(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propioloylpiperidin- 7.73-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;162 5-(2-Methyl-4-phenoxyphenyl)-N-(1-methyl-6-oxopiperidin-3-yl)-4- 6.8oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 163(R)-N-(1-(3-Aminopropanoyl)piperidin-3-yl)-5-(2-methyl-4- 7.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 164N-((3R,5S)-5-Fluoro-1-methylpiperidin-3-yl)-5-(2-methyl-4- 6.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 165N-(1,3-Dimethylpiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 6.6oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 1665-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(2-oxopiperidin-4-yl)-4,5- 6.9dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 167N-((3R,5S)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 7.0oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 168N-((3R,5R)-5-Hydroxy-1-methylpiperidin-3-yl)-5-(2-methyl-4- 6.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 169(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(2-methyl-4- 6.4phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 170(R)-5-(4-(2-Ethylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3- 7.0yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 1715-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(quinuclidin-2-yl)-4,5- 7.0dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 1725-(2-Methyl-4-phenoxyphenyl)-N-(3-methylpiperidin-4-yl)-4-oxo- 6.74,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 1735-(2-Methyl-4-phenoxyphenyl)-N-((6R)-6-methylpiperidin-3-yl)-4- 6.8oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 174(R)-N-(5,5-Difluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 6.6oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 175(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2,6- 7.6difluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 17613C-(R,Z)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5- 7.2(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 17713C-(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5- 7.4(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 178(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4- 7.0(cyclohexyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 179N-((3R,5R)-5-Hydroxypiperidin-3-yl)-5-(2-methyl-4- 7.0phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 180(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)- 6.04-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;181 (R)-N-(1-(2-Cyanoacetyl)piperidin-3-yl)-4-oxo-5-(4- 7.1phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 182(R)-N-(1-Methylpiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 6.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 183(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(2- 7.5(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 184(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1- 7.4propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 185(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4- 7.5cyclopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 186N-((3S,4S)-4-Fluoro-1-methylpyrrolidin-3-yl)-5-(2-methyl-4- 6.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 1875-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazepan-4-yl)-4-oxo-4,5- 6.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 188(R)-N-(1-(3-Methoxy-2,2-dimethylpropanoyl)piperidin-3-yl)-5-(2- 6.7methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 189N-(1-Cyanoazepan-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5- 6.6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 190N-((R)-1-((R)-2,3-Dimethoxypropanoyl)piperidin-3-yl)-5-(2-methyl- 7.04-phenoxyphenyl)-4-oxo-4,5-dihydro-3 H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 1915-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-((R)-1-((R)-pyrrolidine-3- 7.1carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 192N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(2-methyl-4- 6.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 193(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4- 7.3ethoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 194(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-fluorophenyl)-4-oxo-4,5- 6.9dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 195(R,Z)-N-(1-(4-Amino-2-cyano-4-methylpent-2-enoyl)piperidin-3-yl)- 7.45-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 196(R,E)-N-(1-(3-(1-Aminocyclopropyl)-2-cyanoacryloyl)piperidin-3- 6.8yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 197N-((3R,5S)-5-Hydroxypiperidin-3-yl)-5-(2-methyl-4- 6.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 1985-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-((R)-1-((R)-tetrahydrofuran- 7.03-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 199(R,E)-N-(1-(3-Cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4- 6.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 200N-((3S,4R)-4-Hydroxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4- 6.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 201(R)-5-(4-(2-Cyclopropylphenoxy)-2-methylphenyl)-N-(1- 6.6methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 2025-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5- 6.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 203N-(1,2-Dimethylpiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 6.5oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 204(R)-N-(1-Methacryloylpiperidin-3-yl)-5-(2-methyl-4- 6.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 205N-(1-(Cyclopropanecarbonyl)piperidin-3-yl)-5-(2-methyl-4- 6.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 2065-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazepan-3-yl)-4-oxo-4,5- 7.1dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 2075-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-((R)-1-((S)-tetrahydrofuran- 7.13-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 208N-((3S,4R)-4-Methoxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4- 6.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 209(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(5-chlorobenzo[d][1,3]dioxol-4- 7.1yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 210(R)-5-(2-Methyl-4-(m-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)- 6.74-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;211 N-((3S,4R)-4-Methoxypyrrolidin-3-yl)-5-(2-methyl-4- 6.7phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 212(R,E)-N-(1-(2-Cyano-4-(ethylamino)-4-methylpent-2- 7.0enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 213(R)-N-(1-Cyclopropylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)- 6.54-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;214 (R)-5-(4-(3-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin- 6.83-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 215 (R)-5-(2-Fluoro-4-phenoxyphenyl)-N-(1-(3- 7.2methoxypropanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 216(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H- 6.71-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 2175-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(2-(2-oxoimidazolidin-1- 6.5yl)ethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 218N-((3S,4S)-4-Fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)- 6.84-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;219 (R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(tetrahydro-2H- 6.9pyran-4-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 220(R)-5-(4-(2-Hydroxyphenoxy)-2-methylphenyl)-N-(1- 6.5methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 221(R,E)-N-(1-(3-Ethoxyacryloyl)piperidin-3-yl)-5-(2-methyl-4- 6.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 222(R)-5-(2-Fluoro-6-methyl-4-phenoxyphenyl)-N-(1-methylpiperidin- 6.73-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 223 (R)-5-(4-(2-Isopropylphenoxy)-2-methylphenyl)-N-(1- 6.6methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 224N-((3R,5R)-5-Methoxypiperidin-3-yl)-5-(2-methyl-4- 6.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 225(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-methylbut-2- 6.7enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 226(R)-5-(4-(3-(Methoxymethyl)phenoxy)-2-methylphenyl)-N-(1- 6.5methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 227(R)-5-(2-Methyl-4-(2-(trifluoromethoxy)phenoxy)phenyl)-N-(1- 6.5methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 228(R,Z)-N-(1-(3-Cyclopropyl-2-fluoroacryloyl)piperidin-3-yl)-5-(2- 6.6methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 229(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)azetidin-3-yl)-5-(2- 6.7methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 230N-(1-Cyclopropylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 6.4oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 231(R,EZ)-N-(1-(2-Cyano-3-methoxyacryloyl)piperidin-3-yl)-5-(2- 6.8methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 233(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 7.2methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 234(R,EZ)-N-(1-(2-Cyano-4-((2-methoxyethyl)amino)-4-methylpent-2- 7.2enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5- dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 235(R)-5-(2,6-Difluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5- 7.0dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 236N-((3S,4S)-4-Hydroxypyrrolidin-3-yl)-5-(2-methyl-4- 7.0phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 237N1-((E)-4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H- 6.91-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)-N5-(15-oxo-19-((3aS,4R,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)glutaramide; 238(R,E)-N-(1-(2-Cyano-4-methyl-4-(methylamino)pent-2- 6.8enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 239(R,E)-5-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-(2-cyano-3- 7.4cyclopropylacryloyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 2405-(2-Methyl-4-phenoxyphenyl)-N-(1-(3- 6.7(methylsulfonyl)propanoyl)azetidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 241N-((3S,4R)-4-Hydroxypyrrolidin-3-yl)-5-(2-methyl-4- 6.7phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 242(R)-5-(2-Methyl-4-(2-(trifluoromethyl)phenoxy)phenyl)-N-(1- 6.7methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 243N-((3S,4S)-4-Hydroxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4- 6.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 244N-((3S,4S)-4-Methoxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4- 6.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 245N-((3S,4S)-4-Methoxypyrrolidin-3-yl)-5-(2-methyl-4- 6.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 246N-(1-(3-Methoxypropanoyl)azetidin-3-yl)-5-(2-methyl-4- 6.5phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 247(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-methylpent-2- 6.5enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 2485-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazetidin-3-yl)-4-oxo-4,5- 6.5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 249(S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)- 6.64-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;250 (R)-5-(4-(Cyclohexyloxy)-2-methylphenyl)-N-(1-methylpiperidin-3- 6.4yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 251N-(1-Ethylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5- 6.4dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 252N-(Azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro- 6.43H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 253(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-(2- 6.2(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 254(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4- 6.6oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 255(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-fluorophenyl)-4-oxo-4,5- 6.6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 256(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-chlorophenyl)-4-oxo-4,5- 6.6dihydro-3H-1-thia-3,5,8triazaacenaphthylene-2-carboxamide; 257(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-phenyl-4,5-dihydro-3H-1- 6.4thia-3,5,8-triazaacenaphthylene-2-carboxamide; 2585-(2-Methyl-4-phenoxyphenyl)-N-(2-methylpiperidin-4-yl)-4-oxo- 6.54,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 259N-((3R,5R)-5-Methoxy-1-methylpiperidin-3-yl)-4-oxo-5-(4- 6.5phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 260(R)-N-(1-(2-chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl- 6.54-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 261(R,Z)-N-(1-(2-Fluorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4- 6.5phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 262N-(1-Methyl-5-oxopyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 6.4dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 263(R)-N-(1-(2-Fluoro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl- 6.44-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 264(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4- 6.4(pentafluorothio)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 265(S)-5-(2-Methyl-4-phenoxyphenyl)-N-((1-methylpyrrolidin-2- 6.4yl)methyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 266N-((3R,5S)-5-Hydroxy-1-methylpiperidin-3-yl)-5-(2-methyl-4- 6.3phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 267(S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H- 6.3pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 268 N-((3R,5S)-5-Methoxypiperidin-3-yl)-5-(2-methyl-4- 6.3phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 269(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-2-ylmethyl)- 6.34,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 270(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-((tetrahydro-2H- 6.3pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 271(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(p-tolyl)-4,5-dihydro-3H- 6.31-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 272(R)-N-(5,5-Difluoro-1-methylpiperidin-3-yl)-5-(2-methyl-4- 6.3phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 273N-(1-Isopropylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo- 6.34,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 274(R,E)-N-(1-(4,4-Dimethylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl- 6.34-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 2755-(2-Methyl-4-phenoxyphenyl)-N-(2-morpholinoethyl)-4-oxo-4,5- 6.3dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 276(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-2- 6.3ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 277(R,Z)-N-(1-(2-Chlorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4- 6.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 278(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenoxy-2- 6.2(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 279(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(m-tolyl)-4,5-dihydro-3H- 6.21-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 280(R)-5-(4-Chloro-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3- 5.8yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 281(R)-5-(2,3-Dimethyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)- 6.24-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;282 5-(2-Methyl-4-phenoxyphenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-6.2 4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 283 (R)-5-(4-(2-Isopropoxyphenoxy)-2-methylphenyl)-N-(1-6.2 methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 284(R)-5-(4-Cyclobutoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)- 6.24-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;285 (R)-5-(2-Methyl-4-phenoxyphenyl)-N-((1-methylpyrrolidin-2- 6.2yl)methyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 286 (R)-5-(4-(3,5-Difluorophenoxy)-2-methylphenyl)-N-(1-6.2 methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 287(R)-N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-5-(*R)-(2- 6.2methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 288(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3- 6.2(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 289(S)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4- 6.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 290(R)-5-(2-Methyl-4-(p-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4- 6.2oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 291(S)-5-(2-Methyl-4-phenoxyphenyl)-N-(2-(3- 6.1methylmorpholino)ethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 292(R,E)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4- 6.1(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 293(R)-5-(2-Methyl-4-(pyridin-3-yloxy)phenyl)-N-(1-methylpiperidin-3- 6.1yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 294(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-chlorophenyl)-4-oxo-4,5- 6.1dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 295(R)-5-(4-(4-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin- 6.13-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 296 (R)-5-(2-Methyl-4-phenoxyphenyl)-N-(2-(3- 6.1methylmorpholino)ethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 297(R)-5-(4-(Cyclopentyloxy)-2-methylphenyl)-N-(1-methylpiperidin-3- 6.1yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 2985-(2-Methyl-4-phenoxyphenyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)- 6.14-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;299 (R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-6.1 oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;300 (R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)- 6.04,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 301(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2-fluorophenyl)-4-oxo-4,5- 6.0dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 302(R)-5-(4-(2,4-Difluorophenoxy)-2-methylphenyl)-N-(1- 6.0methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 303(R)-5-(5-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-methylpiperidin- 6.03-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 304(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2,4-dimethylphenyl)-4-oxo-4,5- 6.0dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 305(R)-5-(5-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro- 6.02H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 306(R)-5-(2-Methyl-4-(pyridin-2-yloxy)phenyl)-N-(1-methylpiperidin-3- 6.0yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 307(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H- 6.0pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 308(S)-5-(5-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro- 6.02H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 309(S)-N-(1-Benzyl-2-oxoazepan-3-yl)-5-(2-methyl-4-phenoxyphenyl)- 6.04-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;310 (S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-2-ylmethyl)- 6.04,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 311(R)-N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(6-phenoxypyridazin-3- 5.9yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 312N-((3R,5S)-5-Methoxy-1-methylpiperidin-3-yl)-5-(2-methyl-4- 5.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 313(R,EZ)-N-(1-(3-Cyclopropyl-2-(trifluoromethyl)acryloyl)piperidin-3- 5.9yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 314(R)-N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H- 5.91-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 3155-(2-Methyl-4-phenoxyphenyl)-N-(2-morpholino-2-oxoethyl)-4-oxo- 6.94,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 317(R)-5-(2,6-Dimethyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)- 5.84-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;318 (R)-N-(1-(3-Hydroxypropanoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4- 5.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 320(R)-N-(1-Ethylpiperidin-3-yl)-5-(4-(2-isopropylphenoxy)-2- 6.7methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 321(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(5- 7.1chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 322(R)-5-(4-Cyclopropoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)- 5.74-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;323 (S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran- 5.73-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;324 (R)-N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxy-2- 5.7(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 325(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1- 5.7propionylpyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 326(R)-5-(4-(2-Carbamoylphenoxy)-2-methylphenyl)-N-(1- 5.7methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 328(R)-6-Methyl-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5- 5.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 329(R)-N-(1-Cyanopiperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)- 5.74-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;330 (R)-5-(3,5-Dichlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- 5.63H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 331(R)-N-Methyl-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3- 5.5yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 332(R)-5-(4-Isopropoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4- 5.5oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 333(R)-5-(4-Ethoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo- 5.54,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 334(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-(tert-butyl)phenyl)-4-oxo-4,5- 5.5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 336(R)-5-(3-Chlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1- 5.4thia-3,5,8-triazaacenaphthylene-2-carboxamide; 337(R)-N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-phenyl-4,5-dihydro-3H- 5.41-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 338(R)-N-Methyl-5-(2-methyl-4-phenoxyphenyl)-N-(1- 5.4methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 339(S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)- 5.44-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;340 (R)-5-(4-Methoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4- 5.3oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 341(R)-4-Oxo-N-(piperidin-3-yl)-5-(4-(trifluoromethyl)phenyl)-4,5- 5.2dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 342(R)-5-(4-Methoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H- 5.21-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 343(R)-5-(*R)-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-N- 5.3(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 344(R)-5-([1,1′-Biphenyl]-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- 5.03H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 345(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1- <5propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 346(R)-5-(3,4-Dichlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- <53H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 347(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(trifluoromethyl)phenyl)-4,5- <5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 348(R)-4-Oxo-5-phenyl-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8- <5triazaacenaphthylene-2-carboxamide; 349(R)-N-(1-Methylpiperidin-3-yl)-4-oxo-5-(4-phenoxy-2- <5(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 350(R)-5-(4-Methyl-6-phenoxypyridazin-3-yl)-N-(1-methylpiperidin-3- <5yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 351(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(4-methyl-6-phenoxypyridazin- <53-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 352(R)-N-(1-Methylpiperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1- <5thia-3,5,8-triazaacenaphthylene-2-carboxamide; 353(R)-5-(*R)-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1- 5.8methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 354(R)-5-(2-Methyl-4-(pyridin-4-yloxy)phenyl)-N-(1-methylpiperidin-3- <5yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 356(R)-5-(3-(Dimethylamino)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5- <5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 357(R)-N-(1-Acryloylpiperidin-3-yl)-5-isopropyl-4-oxo-4,5-dihydro-3H- 5.11-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 358(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methylpyridin-3-yl)-4-oxo- 5.24,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 359(R)-5-(2-Methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- <53H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 360(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3,4-dichlorophenyl)-4-oxo-4,5- 6.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 361(R)-5-Isopropyl-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia- <53,5,8-triazaacenaphthylene-2-carboxamide; 362(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-chloro-3- 5.4(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 363(R)-N-(1-(3-Methoxy-3-methylbutanoyl)piperidin-3-yl)-5-(2-methyl- 6.94-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 364(R,Z)-N-(1-(3-Acetamidoacryloyl)piperidin-3-yl)-5-(2-methyl-4- 6.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 365(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(*R)- 7.3(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 366(R)-N-(1-(2-Chloroacryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4- 7.1phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 367(R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl- 6.24-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 368(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-5-(2- 7.6methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 369(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1- 7.8(vinylsulfonyl)pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 370(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-trideuteriomethylpiperidin- 7.03-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 371(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-5-(2- 7.0methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 372(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1- 7.6(vinylsulfonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 373(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-5- 7.3(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 374(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylsulfonyl)but-2- 7.0enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 375(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6- 7.9pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 376(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6- 7.8pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 377(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2- 7.5enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 378(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 7.5methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 379(R)-N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6- 7.5pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 380(R)-5-(2-Methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-N-(1- 6.8(trideuteriomethyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 381(R)-5-(2-Methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-N-(1- 7.1methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 382(R,E)-N-(1-(4-Aminobut-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4- 7.3phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 383(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4- 7.2(methylsulfonamido)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 384(R)-N-(1-(2-(Dimethylamino)acetyl)pyrrolidin-3-yl)-5-(2-methyl-4- 7.1phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 385(R,E)-N-(1-(2-Cyanobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4- 7.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 386N-((R)-1-((S)-Azetidine-2-carbonyl)piperidin-3-yl)-5-(2-methyl-4- 6.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 387(R,E)-N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3- 7.8yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 388(R,Z)-N-(1-(2-Fluoro-4-(methylamino)but-2-enoyl)piperidin-3-yl)-5- 7.1(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 389(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(2-(pyrrolidin-1- 7.0yl)acetyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 390(R)-2-(((1-Acryloylpiperidin-3-yl)amino)methyl)-5-(2-methyl-4- 6.9phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one; 391(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2- 7.2(methylamino)acetyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 392(R)-N-(1-(2-Aminoacetyl)pyrrolidin-3-yl)-5-(2-methyl-4- 7.4phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 393(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(2-(piperidin-1- 6.8yl)acetyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 394(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2- 6.8morpholinoacetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 395(R)-N-(1-(2-Chloroacetyl)pyrrolidin-3-yl)-5-(2-methyl-4- 8.0phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 396(R)-N-(1-(2-Chloroacetyl)piperidin-3-yl)-5-(2-methyl-4- 7.8phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 397(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(thiophen-2-yl)phenyl)- 6.44,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 398(R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5- 6.6(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 399(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4- 7.5isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 400(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropoxyphenyl)-4-oxo-4,5- 6.9dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 401(R,E)-N-(1-(3-Cyclopropyl-2-methylacryloyl)piperidin-3-yl)-5-(2- 6.5methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 402(R,EZ)-N-(1-(2-Chloro-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 6.5methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 403(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-morpholinobut-2- 6.4enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 404(R)-N-(1-Acryloylpiperidin-3-yl)-5-(benzo[b]thiophen-5-yl)-4-oxo- 6.14,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 405(R)-5-(4-Isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- 5.53H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 406(R)-5-(4-Isopropoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)- 5.24,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 407(R)-4-Oxo-N-(piperidin-3-yl)-5-(4-(thiophen-2-yl)phenyl)-4,5- 5.1dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 408(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenoxybenzyl)-4,5- 5.1dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 409(R)-N-(1-Methylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxybenzyl)-4,5- 5.0dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 410(R)-5-(Benzo[b]thiophen-5-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- 5.03H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 411(R)-N-(1-Methylpiperidin-3-yl)-4-oxo-5-(4-phenoxybenzyl)-4,5- <5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 412(R)-4-Oxo-5-(4-phenoxybenzyl)-N-(piperidin-3-yl)-4,5-dihydro-3H- <51-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 413(R)-5-(2-Methyl-4-(trifluoromethoxy)phenyl)-4-oxo-N-(piperidin-3- 5.6yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 414(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4- 7.4(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 415(R)-4-Oxo-N-(piperidin-3-yl)-5-(4-(trifluoromethoxy)phenyl)-4,5- 5.2dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 416(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4- 6.7(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 417(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-isopropoxy-2- 5.9methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 418(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(4-isopropoxy-2- 7.8methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 419(R)-N-(1-Acryloylpiperidin-3-yl)-5-(naphthalen-2-yl)-4-oxo-4,5- 5.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 420(R)-N-(1-Acryloylpiperidin-3-yl)-5-(1-benzyl-1H-pyrazol-3-yl)-4- 6.0oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 421(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5- 7.9dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 422(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-benzylphenyl)-4-oxo-4,5- 7.5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 423(R)-5-([1,1′-Biphenyl]-4-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5- 6.3dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 424(R)-N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-4-oxo-5-(4- 7.2phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 425(R)-N-(1-(2-(Dimethylamino)acetyl)pyrrolidin-3-yl)-4-oxo-5-(4- 7.3phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 426(R)-5-([1,1′-Biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- 6.93H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 427(R)-N-(1-Acryloylpiperidin-3-yl)-5-(benzo[b]thiophen-2-yl)-4-oxo- 6.34,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 428(R)-5-(Benzo[b]thiophen-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- <53H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 429(R)-5-(Naphthalen-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1- <5thia-3,5,8-triazaacenaphthylene-2-carboxamide; 430(R)-5-(4-Benzylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1- 6.3thia-3,5,8-triazaacenaphthylene-2-carboxamide; 431(R)-5-(1-Benzyl-1H-pyrazol-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5- <5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 4325-(*S)-(2-Methyl-4-phenoxyphenyl)-N-((4*S)-2-methylpiperidin-4- 7.0yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 4335-(*R)-(2-Methyl-4-phenoxyphenyl)-N-((4*S)-2-methylpiperidin-4- 5.4yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 4345-(*S)-(2-Methyl-4-phenoxyphenyl)-N-((4*R)-2-methylpiperidin-4- 7.3yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 4355-(*R)-(2-Methyl-4-phenoxyphenyl)-N-((4*R)-2-methylpiperidin-4- 5.9yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 436N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(*S)-(2-methyl- 7.34-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 437N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(*R)-(2-methyl- 5.84-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 438(R)-N-(1-(2-Chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(*S)-(2- 6.7methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 439(R)-N-(1-(2-Chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(*R)-(2- 5.7methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 440(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-5- 7.6(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 441(R)-N-(1-Acryloylpyrrolidin-3-yl)-N-methyl-5-(*S)-(2-methyl-4- 5.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 442(R)-N-(1-Acryloylpyrrolidin-3-yl)-N-methyl-5-(*R)-(2-methyl-4- 6.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 443(R)-N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 7.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 444(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropyl-2-methylphenyl)-4- 7.2oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 445(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(4-isopropyl-2-methylphenyl)-4- 6.7oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 446(R)-5-(4-Isopropyl-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5- 5.8dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 447(R)-5-(4-Isopropyl-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4- 5.6oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 450(R,*E)-N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3- 7.6yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 452N-((1-Acryloylpyrrolidin-3-yl)methyl)-4-oxo-5-(4-phenoxyphenyl)- 7.04,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 4534-Oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-ylmethyl)-4,5-dihydro- 6.43H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 454(R)-N-(1-(1H-Imidazole-1-carbonyl)piperidin-3-yl)-5-(2,2- <5difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 455(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-methoxy-3- <5(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 456(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-cyclobutoxy-2-methylphenyl)- 7.74-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;457 (R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-cyclobutoxyphenyl)-4-oxo- 7.64,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 4584-Oxo-N-(2-oxopiperidin-3-yl)-5-(4-phenoxyphenyl)-4,5-dihydro- 6.23H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 459(R)-5-(4-Methoxy-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3- <5yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 460(R)-5-(3-Chloro-4-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5- 5.3dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 461(R)-5-(4-Methyl-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3- 5.0yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 4624-Oxo-5-(4-phenoxyphenyl)-N-((tetrahydrofuran-2-yl)methyl)-4,5- 6.4dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 463N-((3S,4S)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-4-oxo-5-(4- 7.9phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 464N-((3S,4S)-4-Hydroxypyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)- 6.84,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 465(R)-5-(3-Benzylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1- 6.2thia-3,5,8-triazaacenaphthylene-2-carboxamide; 466(R)-4-Oxo-5-(3-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H- 6.71-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 467N-((3R,5S)-5-Methoxypiperidin-3-yl)-5-(*S)-(2-methyl-4- 7.0phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 468N-((3R,5S)-5-Methoxypiperidin-3-yl)-5-(*R)-(2-methyl-4- 5.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 469(*S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin- 7.13-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;470 (*S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin- 5.63-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;471 (*R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin- 5.93-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;472 (*R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin- 7.43-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;473 (R,*E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4- 5.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 474(R,*E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4- 7.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 475(R,*Z)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4- 6.1phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 476(R,*Z)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4- 7.4phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 477(R,*Z)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3- 7.6yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 478(R,*E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3- 7.8yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 479(R,*Z)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3- 6.7yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 480(R,*E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3- 7.2yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 481N-((3R,5R)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(*S)-(2-methyl- 8.24-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 482N-((3R,5S)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(*S)-(2-methyl- 8.04-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 483N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(*S)-(2-methyl- 8.44-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 484N-((3R,5S)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(*S)-(2-methyl-4- 8.0phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 485N-(4-Cyano-1,4-oxazepan-6-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)- 7.94-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;486 N-((3S,4S)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(*S)-(2-methyl-4-7.8 phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 487(R,E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3- 7.6yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 488(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-5-(*S)- 7.2(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 489N-((3S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(*S)-(2-methyl- 7.64-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 490N-((3S,4S)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(*S)-(2-methyl- 7.74-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 491(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)pyrrolidin-3-yl)-5-(*S)- 7.6(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 492(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4- 8.0(methylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 493(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3- 6.9yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 494 (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(3- 8.0(methylsulfonyl)propanoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 495(R)-N-(1-(2-Methoxyacetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4- 7.5phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 496N-(1-Acryloylazetidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4- 7.4oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 497(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-methyl-5-phenoxypyridin-2- 7.9yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 498(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2′,3′-difluoro-[1,1′-biphenyl]-3-7.8 yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 499N-((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(*S)-(2-methyl-4- 7.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 500(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3′-fluoro-[1,1′-biphenyl]-3-yl)-4-8.1 oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;501 (R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-cyclobutoxy-2- 7.9methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 502(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-5-(*S)- 7.9(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 503(R,E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl- 7.84-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 504(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2′-methyl-[1,1′-biphenyl]-3-yl)- 8.04-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;505 (R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4- 7.8(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 506(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridin-3-yl)- 7.94,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 507(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3′-chloro-[1,1′-biphenyl]-3-yl)- 7.84-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;508 N-((3S,4R)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(*S)-(2-methyl-7.7 4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 509(R,EZ)-N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3- 7.9yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 510(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2′-chloro-[1,1′-biphenyl]-3-yl)- 8.04-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;511 (R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-7.8 phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 512(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)- 7.84,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 513(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)- 8.24,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 514(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(*S)- 7.7(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 515(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2′,4′-difluoro-[1,1′-biphenyl]-3-7.7 yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 516(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-benzylphenyl)-4-oxo-4,5- 7.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 517(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3′-methyl-[1,1′-biphenyl]-3-yl)- 7.54-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;518 (S)-N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4- 7.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 519(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclohexylphenyl)-4-oxo-4,5- 7.3dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 520(R,E)-N-(1-(4-Aminobut-2-enoyl)pyrrolidin-3-yl)-5-(*S)-(2-methyl- 8.14-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 521(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4′-methyl-[1,1′-biphenyl]-3-yl)- 7.54-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;522 (R,E)-N-(1-(4-Hydroxybut-2-enoyl)pyrrolidin-3-yl)-5-(*S)-(2- 8.0methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 523N-((3S,4S)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(*S)-(2-methyl- 7.54-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 5245-(*S)-(2-Methyl-4-phenoxyphenyl)-N-((R)-1-((S)-2- 7.8(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 525(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2,2-difluorobenzo[d][1,3]dioxol- 7.55-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 526(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenylpyridin-2-yl)- 7.64,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 527(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5- 8.1dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 528(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyrazin-2-yl)- 7.84,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 529(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-isopropylphenyl)-4-oxo-4,5- 7.6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 530(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1- 8.0(vinylsulfonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 531(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-acryloylpyrrolidin-3-yl)-4-oxo-4,5-7.5 dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 532(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4- 7.4(methylsulfonamido)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 533(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-propylphenyl)-4,5- 7.5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 534(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclobutylphenyl)-4-oxo-4,5- 7.8dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 535(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1- 7.5trideuteriomethylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 536(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-methyl-4-phenoxyphenyl)-4- 7.5oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 537(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenylpyridin-3-yl)- 7.64,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 538(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(pyridin-3-yl)phenyl)- 7.04,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 539(R)-N-(1-(Ethylsulfonyl)piperidin-3-yl)-5-(*S)-(2-methyl-4- 7.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 540(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(pyridin-2-yl)phenyl)- 7.24,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 541(R,E)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(4-(dimethylamino)but-2- 7.2enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 542(R)-N-(1-Isopropylpiperidin-3-yl)-5-(*S)-(2-methyl-4- 7.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 543N-((3S,4S)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-4-oxo-5-(4- 7.5phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 544(S)-1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5- 7.0dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)pyrrolidine-3-carboxamide; 545(R)-1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5- 6.9dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)pyrrolidine-3-carboxamide; 546(R)-N-(1-(2-(Methylamino)acetyl)piperidin-3-yl)-4-oxo-5-(4- 7.4phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 547N-((R)-1-((S)-3-Hydroxy-2-methylpropanoyl)piperidin-3-yl)-5-(2- 7.4methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 548N-((3S,4S)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-4-oxo-5-(4- 6.9phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 549(R,Z)-N-(1-(4-Amino-2-fluorobut-2-enoyl)piperidin-3-yl)-5-(2- 7.2methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 550(R,Z)-N-(1-(4-Amino-2-chlorobut-2-enoyl)piperidin-3-yl)-5-(2- 7.3methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 551(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(2-(methylamino)acetyl)piperidin- 6.83-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 552(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5- 6.8dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 553(R)-5-(3′-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5- 6.8dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 554(R)-5-(2′-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5- 6.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 5555-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-((R)-1-((E)-4- 8.1((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoyl)pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 556(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2-phenoxypyrimidin-5- 7.5yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 557N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(4-isopropoxy-2- 7.3methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 558(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(3-chloro-4-phenoxyphenyl)-4- 7.7oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 559(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5- 8.2(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 560(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-(cyclohexyloxy)phenyl)-4- 7.6oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 561(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-(cyclopentyloxy)phenyl)-4- 7.3oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 562(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-5-(4- 6.7isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 563(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2′-(trifluoromethyl)-[1,1′-7.0 biphenyl]-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 564N-((R)-1-((R)-3-Hydroxy-2-methylpropanoyl)piperidin-3-yl)-5-(2- 7.2methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 565(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-isopropoxyphenyl)-4-oxo-4,5- 7.0dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 566(R)-5-(3-Acetylphenyl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5- 6.6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 567(R)-N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)- 7.44,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 568(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3- 7.4(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 569(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclopropyrphenyl)-4-oxo- 7.04,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 570(R,E)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(4-(dimethylamino)but-2- 7.2enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 571N-((R)-1-((R)-3-Methoxy-2-methylpropanoyl)piperidin-3-yl)-5-(2- 7.0methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 572(R)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(2- 7.1(dimethylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 573(R,E)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(4-(dimethylamino)but-2- 6.6enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 574N-(cis)-1-Acryloyl-3-hydroxypiperidin-4-yl)-4-oxo-5-(4- 6.8phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 575 (R)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(2- 7.3(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 576(R)-N-(1-(2-Methoxyacetyl)piperidin-3-yl)-4-oxo-5-(4- 7.3phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 577(R)-5-(3-Chloro-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5- 7.2dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 5784-Oxo-N-(6-oxopiperidin-3-yl)-5-(4-phenoxyphenyl)-4,5-dihydro- 6.93H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 579N-((3S,4S)-4-Fluoropyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 6.9dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 580(R)-5-(4′-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5- 6.9dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 581(R)-5-(3-Chloro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5- 6.8dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 582(R)-N-(1-Acetylpiperidin-3-yl)-5-(3-chloro-4-phenoxyphenyl)-4-oxo- 6.74,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 583(R)-5-(3-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5- 6.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 584(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-chloro-4-methylphenyl)-4- 6.6oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 585(R)-4-Oxo-5-(2-phenylpyridin-4-yl)-N-(piperidin-3-yl)-4,5-dihydro- 6.53H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 586N-((3R,5R)-5-Hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)- 6.64,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 587(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5- 6.5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 588N-((3S,4S)-4-Methoxypyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)- 6.44,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 589N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-4-oxo-5-(4- 8.1phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 590(R,E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-3-yl)-4-oxo-5-(4- 7.5phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 591(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-cyclobutylpyridin-4-yl)-4- 7.5oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 592(R)-N-(1-Cyanopiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 7.4dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 593(R)-N-(1-(3-Methoxypropanoyl)piperidin-3-yl)-4-oxo-5-(4- 7.2phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 594N-(1-Cyanopiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro- 7.13H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 595(R)-5-(3-Methyl-5-phenoxypyridin-2-yl)-4-oxo-N-(piperidin-3-yl)- 7.14,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 596(E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-4-yl)-4-oxo-5-(4- 6.9phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 597 N-(1-(3-Methoxypropanoyl)piperidin-4-yl)-4-oxo-5-(4-6.9 phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 598 (R)-N-(1-Acryloylpiperidin-3-yl)-3-amino-4-((3- 6.5cyclobutoxyphenyl)amino)thieno[2,3-b]pyridine-2-carboxamide; 599(R)-5-([1,1′-Biphenyl]-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro- 6.53H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 6002-((1-Acryloylpiperidin-3-yl)amino)-5-(2-methyl-4-phenoxyphenyl)- 6.53H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one; 601(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(2- 6.4(methylamino)acetyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 602(R)-4-Oxo-5-(2-phenylpyridin-4-yl)-N-(pyrrolidin-3-yl)-4,5-dihydro- 6.43H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 603(R)-5-(3-Cyclobutylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- 6.33H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 604(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenylpyridin-2-yl)- 6.34,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 605(R)-5-(4-Cyclobutoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)- 6.34,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 6062-((1-Acryloylpiperidin-4-yl)amino)-5-(2-methyl-4-phenoxyphenyl)- 6.23H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one; 607(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-3- 6.2(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 6085-(4-Isopropoxy-2-methylphenyl)-4-oxo-N-((R)-1-((E)-4-((4aR,7aS)- 6.2tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 609(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-cyclobutoxy-2- 6.3methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 610(R)-4-Oxo-5-(4-phenylpyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro- 6.23H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 611(3R,5R)-tert-Butyl 3-hydroxy-5-(4-oxo-5-(4-phenoxyphenyl)-4,5- 6.2dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate; 612(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-(oxetan-3-yloxy)phenyl)-4- 6.1oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 613(R)-5-(3-(Cyclopentyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5- 6.1dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 614N-((3S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(4-isopropoxy- 6.12-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 615N-(trans-3-Hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 6.1dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 616(R)-5-(3-(Cyclohexyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5- 6.1dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 617trans-tert-Butyl 3-hydroxy-4-(4-oxo-5-(4-phenoxyphenyl)-4,5- 6.0dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate; 618(R)-4-Oxo-5-(5-phenylpyridin-3-yl)-N-(piperidin-3-yl)-4,5-dihydro- 6.03H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 619(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methoxypyrimidin-5-yl)-4- <6oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 620(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(trifluoromethoxy)phenyl)-4,5- <6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 621(R)-5-(3-Cyclobutoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- <63H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 622(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(pyridin-2-yl)phenyl)-4,5- <6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 623(R)-4-Oxo-5-(6-phenylpyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro- <63H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 624(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4- 5.9(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 625 (3S,4S)-tert-Butyl3-fluoro-4-(4-oxo-5-(4-phenoxyphenyl)-4,5- 5.9dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidine-1-carboxylate; 626(R)-5-(4-Cyclobutoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- 5.93H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 627 tert-Butyl4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia- 5.93,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate; 628(R)-tert-Butyl 3-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia- 5.83,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate; 629(R)-5-(3-Cyclohexylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- 5.93H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 630(R)-5-(3-Isopropylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H- 5.91-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 631(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(pyridin-4-yl)phenyl)- 5.94,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 632(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-(oxetan-3-yl)phenyl)-4-oxo- 5.94,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 633(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropoxy-3-methylphenyl)- 5.84-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;634 (R)-5-(2-Cyclobutylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5- 5.8dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 635(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridin-2-yl)- 5.84,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 636(R)-5-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-N-(piperidin-3- 5.7yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 637(R)-5-(3-Isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- 5.73H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 638(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-(tert-butyl)phenyl)-4-oxo-4,5- 5.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 639(3S,4S)-tert-Butyl 3-methoxy-4-(4-oxo-5-(4-phenoxyphenyl)-4,5- 5.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidine-1-carboxylate; 640(R)-N-(1-Acryloylpiperidin-3-yl)-5-(5-isopropoxy-2-methylphenyl)- 5.64-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;641 (R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-(tert-butylsulfonyl)phenyl)-4-5.6 oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;642 (R)-5-(4-Hydroxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H- 5.31-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 643(R)-5-(3-Acetylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1- 5.1thia-3,5,8-triazaacenaphthylene-2-carboxamide; 644(R)-5-(5-Isopropoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5- <5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 645(R)-4-Oxo-5-(6-phenoxypyridin-2-yl)-N-(piperidin-3-yl)-4,5- <5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 646(R)-5-(3-(tert-Butyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- <53H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 647(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(pyridin-4-yl)phenyl)-4,5- <5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 648(R)-tert-Butyl 3-(5-(3-(tert-butyl)phenyl)-4-oxo-4,5-dihydro-3H-1- <5thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1- carboxylate;649 (R)-tert-Butyl 3-(5-(3-acetylphenyl)-4-oxo-4,5-dihydro-3H-1-thia- <53,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate; 650(R)-5-(4-(tert-Butylsulfonyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5- <5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 651(R)-tert-Butyl 3-(5-(4-(tert-butylsulfonyl)phenyl)-4-oxo-4,5-dihydro- <53H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate; 652 (R)-tert-Butyl3-(5-(4-(tert-butoxy)phenyl)-4-oxo-4,5-dihydro-3H-1- <5thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1- carboxylate;653 (R)-tert-Butyl3-(5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-4,5- <5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate; 654 (R)-tert-Butyl3-(5-(6-cyclobutoxypyridin-3-yl)-4-oxo-4,5-dihydro- <53H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate; 655N-((3R,4R)-1-Acryloyl-4-hydroxypiperidin-3-yl)-4-oxo-5-(4- 8.0phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 656(R)-5-(3-Methyl-5-phenoxypyrazin-2-yl)-4-oxo-N-(piperidin-3-yl)- 6.24,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 657(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-methyl-5-phenoxypyrazin-2- 7.7yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 658N-((3R,4R)-4-Hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)- 6.64,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 659N-(cis-3-Hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 6.6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 661(R)-N-(1-Acryloylpiperidin-3-yl)-5-(R)-(2-methyl-6-phenoxypyridin- 8.33-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 662 (R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-methyl-6-8.1 phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 663(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(4-methyl-6- 8.0phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 664(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(4-methyl-2- 7.6phenoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 665(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyrimidin-2- 7.8yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 666(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(2-methyl-6- 6.3phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 667(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-6-phenoxypyridin-3- 7.9yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 668N-(cis-4-Acrylamidotetrahydrofuran-3-yl)-5-(*S)-(4-methyl-6- 7.8phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 669(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutyl-4- 8.1methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 670(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3- 8.2yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 671(R)-N-(1-Acryloylpiperidin-3-yl)-5-(6-isobutyl-4-methylpyridin-3- 7.6yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 672(R)-N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxy-4-methylpyridin- 7.63-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 673(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2′,3′-difluoro-[1,1′-biphenyl]-3-8.2 yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 674N-((3R,5S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2′,3′-difluoro- 8.2[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 675(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-((tetrahydro- 7.22H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 676(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(3-methyl-2-phenylpyridin- 7.64-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 677(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-cyclohexylpyridin-4-yl)-4- 7.3oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 678(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenylpyridazin-4-yl)- 7.34,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 679N-((3R,5S)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2′,3′-difluoro- 7.8[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 680(R)-N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(6-phenoxypyridin-3-yl)- 7.34,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 681N-((R)-1-((*E)-3-((S)-1-Acetylpyrroridin-2-yl)-2- 7.7cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 682(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-cyclobutoxy-2- 7.3methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 683N-((R)-1-((E)-3-((R)-1-Acetylpyrrolidin-2-yl)-2- 7.7cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 6845-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-((R)-1-((E)-4- 7.5((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 685(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenylpyrimidin-4-yl)- 8.14,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 686(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-chloro-4-phenoxyphenyl)-4- 7.6oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 687(R)-N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxypyridin-3-yl)-4- 7.5oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 688(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-[1,1′-biphenyl]-3-yl)- 7.54-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;689 (R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-isobutylphenyl)-4-oxo-4,5- 7.6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 690(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-6- 7.6phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 691(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(4-methyl-6- 6.0phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 692(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-cyclopentylpyridin-4-yl)-4- 8.0oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 693(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-(cyclopentyloxy)-2- 7.9methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 694(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4- 7.1oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 695(R)-N-(1-Acryloylpiperidin-3-yl)-5-(5-methyl-2-phenylpyridin-4-yl)- 7.34-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;696 (R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-(2-isopropoxyethoxy)-2- 6.9methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 697(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-isopropylpyridin-4-yl)-4-oxo- 6.94,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 698(R)-N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)- 7.54,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 699(R)-N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-phenoxypyrazin-2-yl)- 7.24,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 700(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-cyclobutoxy-4- 8.1methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 701(R)-5-([2,3′-Bipyridin]-4-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-7.2 dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 702(R)-5-(*S)-(4-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(pyrrolidin-3- 6.8yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 703(R,E)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(4-(dimethylamino)but-2- 7.8enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 704(R)-N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxy-2-methylpyridin- 6.63-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 705(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(3-isopropylphenyl)-4-oxo-4,5- 6.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 706(R)-5-(2′,3′-Difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-7.7 4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 707N-((1RS,2RS)-2-Aminocyclopentyl)-5-(*S)-(4-methyl-6- 6.7phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 708(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(tetrahydro-2H-pyran- 6.54-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 709(R)-5-([2,2′-Bipyridin]-4-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-6.7 dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 710(R)-5 -(2′,3′-Difluoro-[1,1′-biphenyl]-3-yl)-N-(1-methylpiperidin-3- 7.4yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 711(R)-5-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)- 6.64,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 713(R)-5-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3- 6.6yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 714(R)-N-(1-(Methylglycyl)piperidin-3-yl)-4-oxo-5-(2-phenylpyridin-4- 6.5yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 715(R)-5-(*S)-(4-Methyl-2-phenoxypyrimidin-5-yl)-4-oxo-N- 6.3(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 716 (R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-6-8.0 phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 717(R)-5-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(pyrrolidin-3- 6.4yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 718N-((3S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-4-oxo-5-(2- 6.3phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 719(R)-4-Oxo-5-(5-phenoxypyrimidin-2-yl)-N-(piperidin-3-yl)-4,5- 6.3dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 720(R)-5-(2-Cyclopentylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5- 6.2dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 721(R)-5-(3-Isobutylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H- 6.21-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 722(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutyl-4- 6.4methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 723(R)-4-Oxo-5-(6-phenylpyrimidin-4-yl)-N-(piperidin-3-yl)-4,5- 6.1dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 724(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(4-methyl-2- 6.1phenoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 725(R)-5-(4-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5- 6.1dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 726(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-cyclobutoxy-4- 6.0methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 727(R)-5-(2-Isopropylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5- <6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 728(R)-5-(*R)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(pyrrolidin- <63-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;729 (R)-5-(5-Methyl-2-phenylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-<6 dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 730(R)-5-(4-(2-Isopropoxyethoxy)-2-methylphenyl)-4-oxo-N-(piperidin- <63-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;731 (R)-5-(2-Cyclohexylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5- <6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 732(R)-N-(1-Acryloylpiperidin-3-yl)-5-(6-isopropoxy-2-methylpyridin- <63-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 733(R)-5-(3-Methyl-2-phenylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5- <6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 734(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-phenylpyridin-4-yl)- <64-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;735 (R)-5-(2-Methyl-6-phenylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-<6 dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 736(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-cyclobutoxy-2- <6methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 737(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(3-methyl-2-phenylpyridin- <64-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 738(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(tetrahydro-2H-pyran-4- <6yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 739 (R)-tert-Butyl3-(4-oxo-5-(3-(tetrahydro-2H-pyran-4-yl)phenyl)-4,5- <6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate; 740(R)-4-Oxo-5-(6-phenylpyridazin-4-yl)-N-(piperidin-3-yl)-4,5- <6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 741(R)-4-Oxo-5-(6-phenoxypyridin-3-yl)-N-(pyrrolidin-3-yl)-4,5- 5.9dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 742(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-((tetrahydro- 5.82H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 743 (R)-tert-Butyl3-(5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5- 5.8dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate; 744(R)-5-(6-Cyclobutoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5- 5.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 745N-((3*S,4*R)-4-Acrylamidotetrahydrofuran-3-yl)-5-(*S)-(4-methyl- 8.16-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 746(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-methyl-2- 8.1phenoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 747(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-isobutyl-4- 7.5methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 748(R)-N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(2-phenoxypyrimidin-5- 6.8yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 749(R)-N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-phenoxypyrimidin-2- 7.3yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 750(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-isobutylphenyl)-4-oxo-4,5- 6.6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 751(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenylpyridazin-3-yl)- 6.74,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 752N-((*3R,*4S)-4-Acrylamidotetrahydrofuran-3-yl)-5-(*S)-(4-methyl- 6.46-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 753(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isopropoxy-2- 6.2methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 754(R)-5-(4-Isobutylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H- <61-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 755(R)-4-Oxo-5-(5-phenylpyridazin-3-yl)-N-(piperidin-3-yl)-4,5- <6dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 756(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(6-isobutyl-4- <6methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 757(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isopropoxy-2- <6methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 759(R)-5-(*S)-(6-Isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3- 6.7yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 760(R)-5-(*R)-(6-Isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin- <63-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;761 (R)-5-(*S)-(6-(Cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N- 7.1(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 762(R)-5-(*R)-(6-(Cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N- <6(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 764(R)-N-(1-Acryloylpiperidin-3-yl)-5-(6-isobutyl-2-methylpyridin-3- 6.3yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 765(R)-5-(*S)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-N-(1- 6.5propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 766(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutoxy-4- 8.2methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 767(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutoxy-4- <6methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 768(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-(cyclopentyloxy)-4- 8.2methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 769(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-(cyclopentyloxy)-4- 6.2methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 770(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-((tetrahydro-2H- <6pyran-4-yl)oxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 771(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-((2-methylpyridin-3- 7.4yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 772(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((6-methylpyridin-2- 7.7yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 773(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((2-methylpyridin-3- 7.4yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 774(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridin-3- 7.9yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 775(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-((6-methylpyridin-2- 7.5yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 776(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-(cyclopentyloxy)-4- 8.1methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 777(R)-N-(1-Acryloylpiperidin-3-yl)-5-(5-(2-fluorophenoxy)pyridin-2- 8.3yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 778(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pyridin-2- 8.0yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 779(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-isobutoxy-4- 8.0methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 780Nl-(15-Oxo-19-((3aR,4R,6aS)-2-oxohexahydro-1H-thieno[3,4- 6.3d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)-N5-((E)-4-oxo-4-(3-(4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)but-2-en-1-yl)glutaramide; 781(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pyridin-2- 7.4yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 782(R,EZ)-N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3- 7.7yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 783(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((6-methylpyridin-3- 7.1yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 784(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pyridazin-3- 7.4yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 785N-((R)-1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(((S)- 7.1tetrahydrofuran-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 786(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-((5-methylpyridin-2- 6.9yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 787N-((R)-1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(((R)- 6.6tetrahydrofuran-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 7881-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro- 6.73H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide; 789(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isopropoxy-4- 8.1methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 790(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pyridazin-3- 6.7yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 791(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3- 6.6yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 792 (R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutyl-2-6.4 methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 793(R)-5-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N- 6.8(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 794(R)-5-(*S)-(6-Isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin- 6.53-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;795 (S)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-6.4 4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 7962-(4-Acryloylpiperazin-1-yl)-5-(2-methyl-4-phenoxyphenyl)-3H-1- 6.3thia-3,5,8-triazaacenaphthylen-4(5H)-one; 797(R)-5-(*S)-(6-(Cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N- 6.3(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 798(R)-5-(*S)-(6-Isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin- 6.33-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;799 (R)-5-(2-Methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-N-(1- 6.2propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 800(R)-N-(1-Acetylpiperidin-3-yl)-5-(2-methyl-4-(pyridin-2- 6.2yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 801(E)-1-(2-Cyano-3-cyclopropylacryloyl)-N-(5-(2-methyl-4- 6.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide; 8021-Cyano-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H- 6.11-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide; 803(R)-N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-(pyridazin-3- 6.1yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 804(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isopropoxy-4- 6.1methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 805N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia- 6.03,5,8-triazaacenaphthylen-2-yl)-1-propionylpiperidine-4- carboxamide;806 (R)-5-(*R)-(6-Isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-<6 3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 807(R)-4-Oxo-N-(1-propionylpiperidin-3-yl)-5-(4-(pyridin-2- <6yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 808(R)-N-(1-Acetylpiperidin-3-yl)-4-oxo-5-(4-(pyridin-2-yloxy)phenyl)- <64,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 809(R)-5-(2-Methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-N-(1- <6propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 810(R)-N-(1-Acetylpiperidin-3-yl)-5-(2-methyl-4-(pyridazin-3- <6yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 811(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3- <6yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 812 (R)-N-(1-Acetylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3-<6 yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 813(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-((tetrahydro- <62H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 814(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-((tetrahydro- <62H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 815(R)-N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutyl-2- <6methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 816(E)-1-(2-Cyano-4,4-dimethylpent-2-enoyl)-N-(5-(2-methyl-4- 6.0phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide; 8171-(2-Cyanoacetyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5- 6.0dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide; 818N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia- 5.93,5,8-triazaacenaphthylen-2-yl)-1-propionylpiperidine-3- carboxamide;819 1-(2-Cyanoacetyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5- 5.9dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide; 8201-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro- 5.93H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide; 8211-Ethyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1- 5.8thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide; 8221-Cyano-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H- 5.81-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide; 8231-Methyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H- 5.51-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide; 834(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1- 8.0(vinylsulfonyl)pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 835(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 8.0methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 836(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 7.9fluoro-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 837(R)-N-(1-Cyanopyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 7.9oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 838(R)-N-(1-(2-Cyanoacetyl)pyrrolidin-3-yl)-5-(2-methyl-4- 7.9phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 839(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 7.9oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 840(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5- 7.8(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 841(R)-N-(1-(3-Methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4- 7.7phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 842(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2′,3′-difluoro-4-methyl-[1,1′- 7.7biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 843(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpyrrolidin- 7.63-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;844 (R,E)-N-(l-(2-Cyano-3-cyclopropylacryloyl)pyrrolidin-3-yl)-5-(2- 7.6methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 845(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(4- 7.6(pyrrolidin-1-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 846(R)-N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridin-2- 7.6yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 847 (R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(3-((2- 7.6cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 8485-(2-Methyl-4-phenoxyphenyl)-N-((R)-1-((R)-2- 7.6(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 849N-((R)-1-((R)-Azetidine-2-carbonyl)piperidin-3-yl)-5-(2-methyl-4- 7.6phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 850(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 7.6methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 851(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5- 7.5(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 852(R)-N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 7.5oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 8535-(2-Methyl-4-phenoxyphenyl)-N-((R)-1-((S)-2- 7.5(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 854(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5- 7.5(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 8555-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-N-(1- 7.5methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 856(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(2- 7.5methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 8575-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo- 7.5N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 8585-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-4-yl)-4-oxo- 7.54,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 859(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 7.4methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 860(R)-4-Oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H- 7.41-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 861(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(3- 7.3((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 862(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4- 7.3methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 863(S)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 7.3oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 864(S)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 7.3oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 8655-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-4-yl)-4,5- 7.3dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 866(R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5- 7.3(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 867(R,E)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(4-(pyrrolidin-1- 7.3yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 868(R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-3-yl)-5- 7.3(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 869(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5- 7.3dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 8705-(4-(2-Methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3- 7.3yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 871(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin- 7.33-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;872 N-(1-Cyanopiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo- 7.24,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 873(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4- 6.9oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 874(R)-N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4- 7.2phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 875(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 7.2methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 8765-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-((R)-1-((R)-pyrrolidine-2- 7.1carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 877(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 7.1methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 878(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4- 7.1methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 879(S)-N-(1-Formylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 7.1oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 880(R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(2- 7.1methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 881(R)-N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-(pyridin-2- 7.1yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 882N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)- 7.04-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;883 N-(1-Cyanopiperidin-3-yl)-5-(4-(2-methoxyphenoxy)-2- 7.0methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 884N-(1-Cyanopiperidin-4-yl)-5-(4-(2-methoxyphenoxy)-2- 7.0methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 885(R)-N-(1-Formylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 7.0oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 886(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5- 7.0(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 887(S)-N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4- 7.0oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 888(R)-N-(1-Acetylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 7.0dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 8895-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5- 7.0dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 890N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo- 7.04,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 891(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3- 7.0yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 892(S)-N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4- 7.0phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 8935-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-((R)-1-((S)-pyrrolidine-2- 7.0carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 894(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-(3-((2- 7.0cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 895(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 7.0methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 896(E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(4-(2- 6.9methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 897(E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(2- 6.8methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 8985-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo- 6.84,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 899(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 6.8methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 900(R,E)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(4-(piperidin-1- 6.8yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 901(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 6.8methyl-3-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 902(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 6.8fluoro-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 9035-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)- 6.84,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 904(S,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(2- 6.7methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 905(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)pyrrolidin-3-yl)-5-(2- 6.7methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 906(R)-N-(1-(3-Chloropropanoyl)piperidin-3-yl)-4-oxo-5-(5- 6.7phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 9075-(4-(2-Methoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3- 6.7yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 908(R)-N-(1-(2-(Azetidin-1-yl)acetyl)piperidin-3-yl)-5-(2-methyl-4- 6.7phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 9094-Oxo-5-(4-phenoxyphenyl)-N-(tetrahydro-2H-pyran-4-yl)-4,5- 6.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 910(R)-N-(1-Methylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 6.7dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 911(R)-4-Oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H- 6.61-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 912(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5- 6.5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 913(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-5-(4- 6.5isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 914(R)-N-(1-Benzoylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 6.5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 915(R)-4-Oxo-5-(5-phenoxypyridin-2-yl)-N-(piperidin-3-yl)-4,5- 6.5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 916(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-4-yl)-5-(2- 6.4methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 9175-(4-(2-Methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-4- 6.4yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 9185-(4-(2-Methoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-4- 6.4yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 919(R)-5-(4-(Cyclopentyloxy)-2-methylphenyl)-4-oxo-N-(piperidin-3- 6.4yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 920N-(1-Methylpiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro- 6.43H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 921(E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-4-yl)-5-(2- 6.3methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 922(R)-4-Oxo-5-(6-phenoxypyridin-3-yl)-N-(piperidin-3-yl)-4,5- 6.3dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 923(R)-5-(4-Isopropoxy-2-methylphenyl)-N-(1-(2- 6.3(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 924(S)-N-(1-Acetylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 6.3dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 925(R)-N-(1-Benzylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 6.3dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 9264-Oxo-5-(4-phenoxyphenyl)-N-(piperidin-4-yl)-4,5-dihydro-3H-1- 6.2thia-3,5,8-triazaacenaphthylene-2-carboxamide; 9274-Oxo-5-(4-phenoxyphenyl)-N-(2-(pyrrolidin-1-yl)ethyl)-4,5- 6.2dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 9284-Oxo-5-(4-phenoxyphenyl)-N-(2-(piperazin-1-yl)ethyl)-4,5-dihydro- 6.23H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 929N-(1-Acryloylpiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo- 6.14,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 930(S)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4- 6.0oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 931(S)-N-(1-Methylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 6.1dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 9324-Oxo-5-(4-phenoxyphenyl)-N-(2-(piperidin-1-yl)ethyl)-4,5-dihydro- 6.13H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 933N-(2-Morpholinoethyl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H- 6.11-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 934(S)-4-Oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H- 6.11-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 935N-(2-(4-Methylpiperazin-1-yl)ethyl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 6.0dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 936(R)-N-(1-Acetylpiperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4- <6oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide; 937(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(pyridin-3-yl)phenyl)-4,5- 6.0dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 938(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- 6.0methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 939(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5- 6.0(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 940(S)-N-(1-Benzoylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 5.9dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 941(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3,5-dichlorophenyl)-4-oxo-4,5- 5.8dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 942(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5- 5.6(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 943(R)-N-(1-Acryloylpiperidin-3-yl)-5-(3-(dimethylamino)phenyl)- 5.64-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2- carboxamide;944 N-(1-(2-Cyanoacetyl)piperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-5.6 4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 945(S)-N-(1-Benzylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5- 5.5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 946(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4- 5.4methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 9475-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-4-yl)- 5.44,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 948(R)-N-(1-Acryloylpiperidin-3-yl)-5-(4-aminophenyl)-4-oxo-4,5- 5.2dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 949(R)-5-(4-(Dimethylamino)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5- 5.2dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 950(R)-4-Oxo-N-(piperidin-3-yl)-5-(m-tolyl)-4,5-dihydro-3H-1-thia- 5.13,5,8-triazaacenaphthylene-2-carboxamide; 951(R)-5-(4-Chlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1- 5.1thia-3,5,8-triazaacenaphthylene-2-carboxamide; 952(R)-4-Oxo-N-(piperidin-3-yl)-5-(p-tolyl)-4,5-dihydro-3H-1-thia- 5.13,5,8-triazaacenaphthylene-2-carboxamide; 953(R)-5-(4-Fluorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1- 5.1thia-3,5,8-triazaacenaphthylene-2-carboxamide; 954(R)-5-(4-(tert-Butyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- 5.03H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 955(R)-5-(4-Isopropoxy-3-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5- <5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 956(R)-5-(4-Aminophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1- <5thia-3,5,8-triazaacenaphthylene-2-carboxamide; 957(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2- <5methyl-3-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 958(R)-5-(*S)-(6-Isopropoxy-4-methyrpyridin-3-yl)-4-oxo-N- <6(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 959(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-isopropoxy-4- 7.5methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 974(R)-N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-6-(pyridazin-3- 5.6yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide; 975(R)-N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-(pyridazin-3- 5.0yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;

Aspects

-   -   Aspect 1. A compound of formula I′:

-   wherein-   R¹ is H or C₁₋₆alkyl;-   R² is —C₀₋₆alk-piperidinyl; —C₀₋₆alk-pyrrolidinyl;    —C₀₋₆alk-oxazepanyl; —C₀₋₆alk-azetidinyl; —C₀₋₆alk-aziridinyl;    —C₀₋₆alk-azepanyl; —C₀₋₆alk-quinuclidinyl; —C₀₋₆alk-imidazolidinyl;    —C₀₋₆alk-piperazinyl; —C₀₋₆alkmorpholinyl;    —C₀₋₆alk-tetrahydropyranyl; or —C₀₋₆alk-tetrahydrofuranyl wherein    the R² is optionally substituted with 1, 2, or 3 substituents    independently selected from the group consisting of    -   —NR⁸—C(O)—C(R³)═CR⁴(R⁵); —C(O)—C(R³)═CR⁴(R⁵); oxo; halogen; —CN;        —OH; —NR⁶R⁷; —C₁₋₆alkyl; —C₁₋₆alk-OH; —OC₁₋₆alkyl;        —C₃₋₆cycloalkyl; —C₁₋₆haloalkyl; —C₁₋₆alkaryl; —SO₂—C₁₋₆alkyl;        —SO₂—C₂₋₆alkenyl; —C(O)H; —C(O)—C₁₋₆alkyl; —C(O)—C₃₋₆cycloalkyl;        —C(O)—C₁₋₆haloalkyl; —C(O)—C₂₋₆alkynyl; —C(O)—C₆₋₁₀aryl;        —C(O)-heteroaryl; —C(O)—C₁₋₆alk-CN; —C(O)—C₁₋₆alk-OH;        —C(O)—C₁₋₆alk-SO₂—C₁₋₆alkyl; —C(O)—O—C₁₋₆alkyl;        —C(O)—C₁₋₆alk-NR⁶R⁷; —C(O)—C₁₋₆alk-O—C₁₋₆alkyl wherein the        —C₁₋₆alk- is optionally substituted with —OH, —OC₁₋₆alkyl, or        —NR⁶R⁷; and —C(O)—C₀₋₆alk-heterocycloalkyl wherein the -alk- is        optionally substituted with oxo and the heterocycloalkyl is        optionally substituted with —C₁₋₆alkyl; wherein        -   R³ is H; —CN; halogen; —C₁₋₆haloalkyl; or —C₁₋₆alkyl;        -   R⁴ and R⁵ are each independently H; halogen; —C₁₋₆alkyl;            —OC₁₋₆alkyl; —C₀₋₆alk-C₃₋₆cycloalkyl optionally substituted            with C₁₋₆alkyl; —C₀₋₆alk-heterocycloalkyl optionally            substituted with —C(O)C₁₋₆alkyl or —C₁₋₆alkyl; —C₁₋₆alk-OH;            —C₀₋₆alk-NR⁶R⁷; —C₁₋₆alk-O—C₁₋₆alkyl;            —C₁₋₆alk-NH—C₀₋₆alk-O—C₁₋₆alkyl; —C₁₋₆alk-NHSO₂—C₁₋₆alkyl;            —C₁₋₆alk-SO₂—C₁₋₆alkyl; —NHC(O)—C₁₋₆alkyl; or            -linker-PEG-Biotin; and        -   R⁶ and R⁷ are each independently H; —C₁₋₆alkyl;            —C₃₋₆cycloalkyl; C(O)H, or —CN; and        -   R⁸ is H or C₁₋₆alkyl;-   A is a bond, pyridyl; phenyl; napthalenyl; pyrimidinyl; pyrazinyl;    pyridazinyl; benzo[d][1,3]dioxolyl optionally substituted with    halogen; benzothiophenyl; or pyrazolyl; optionally substituted with    1, 2, or 3 substituents independently selected from the group    consisting of —C₁₋₆alkyl; halogen; —SF₅; —OC₁₋₆alkyl;    —C(O)—C₁₋₆alkyl; and —C₁₋₆haloalkyl;-   E is —O—; a bond; —C(O)—NH—; —CH₂—; or —CH₂—O—;-   G is H; —C₃₋₆cycloalkyl; -phenyl; -thiophenyl; —C₁₋₆alkyl;    -pyrimidinyl; -pyridyl; -pyridazinyl; -benzofuranyl; —C₁₋₆haloalkyl;    -heterocycloalkyl that contains an oxygen heteroatom;    -phenyl-CH₂—O-phenyl; —C₁₋₆alk-O—C₁₋₆alkyl; —NR⁶R⁷; —SO₂C₁₋₆alkyl;    or —OH; wherein the phenyl; thiophenyl; pyrimidinyl; pyridyl;    pyridazinyl; or benzofuranyl is optionally substituted with 1, 2, or    3 substituents independently selected from the group consisting of    halogen; —C₁₋₆alkyl; —C₁₋₆haloalkyl; —OC₁₋₆haloalkyl;    —C₃₋₆cycloalkyl; —OC₁₋₆alkyl; —CN; —OH; —C₁₋₆alk-O—C₁₋₆alkyl;    —C(O)—NR⁶R⁷; and —C(O)—C₁₋₆alkyl;-   or a stereoisomer or isotopic variant thereof;-   or a pharmaceutically acceptable salt thereof.    -   Aspect 2. The compound of aspect 1, wherein R¹ is H.    -   Aspect 3. The compound of aspect 1 or aspect 2, wherein R² is        —C₀₋₆alk-piperidinyl, —C₀₋₆alk-pyrrolidinyl,        —C₀₋₁alk-piperidinyl, —C₀₋₁alk-pyrrolidinyl, —C₀alk-piperidinyl,        or -C₀alk-pyrrolidinyl.    -   Aspect 4. The compound of aspect 1 or aspect 2, wherein R² is        —C₀₋₆alk-azetidinyl; —C₀₋₆alk-azepanyl; —C₀₋₆alk-quinuclidinyl;        —C₀₋₆alk-imidazolidinyl; or —C₀₋₆alkpiperazinyl.    -   Aspect 5. The compound of aspect 1 or aspect 2, wherein R² is        —C₀₋₆alk-oxazepanyl or —C₀₋₆alkmorpholinyl.    -   Aspect 6. The compound of aspect 1 or aspect 2, wherein R² is        —C₀₋₆alk-tetrahydropyranyl or —C₀₋₆alk-tetrahydrofuranyl.    -   Aspect 7. The compound of any one of the preceding aspects,        wherein R² is unsubstituted.    -   Aspect 8. The compound of any one of the preceding aspects,        wherein R² is substituted with 1 or 2 substitutents, preferably        R² is substituted with 1 substitutent.    -   Aspect 9. The compound of aspect 8, wherein R² is substituted        with oxo.    -   Aspect 10. The compound of aspect 8 or aspect 9, wherein R² is        substituted with halogen; —CN; —OH; —C₁₋₆alkyl; —C₁₋₆haloalkyl;        —C₁₋₆alk-OH; —OC₁₋₆alkyl; —C₃₋₆cycloalkyl; —NR⁶R⁷; or        —C₁₋₆alkaryl.    -   Aspect 11. The compound of any one of aspects 8-10, wherein R²        is substituted with —C(O)H; —C(O)—C₁₋₆alkyl;        —C(O)—C₃₋₆cycloalkyl; —C(O)—C₁₋₆haloalkyl; —C(O)-alkynyl;        —C(O)—C₆₋₁₀aryl; —C(O)—C₁₋₆alk-CN; —C(O)—C₁₋₆alk-OH;        —C(O)—O—C₁₋₆alkyl; —C(O)—C₁₋₆alk-NR⁶R⁷; or        —C(O)—C₁₋₆alk-O—C₁₋₆alkyl wherein the —C₁₋₆alk- is optionally        substituted with —OH, —OC₁₋₆alkyl, or —NR⁶R⁷.    -   Aspect 12. The compound of any one of aspects 8-11, wherein R²        is substituted with —C(O)-heteroaryl or        —C(O)—C₀₋₆alk-heterocycloalkyl wherein the heterocycloalkyl is        optionally substituted with —C₁₋₆alkyl.    -   Aspect 13. The compound of any one of aspects 8-12, wherein R²        is substituted with —SO₂alkyl; —C(O)—C₁₋₆alk-SO₂—C₁₋₆alkyl; or        —SO₂—C₂₋₆alkenyl.    -   Aspect 14. The compound of any one of aspects 8-13, wherein R²        is substituted with —NR⁸—C(O)—C(R³)═CR⁴(R⁵).    -   Aspect 15. The compound of aspect 14, wherein R⁸ is H.    -   Aspect 16. The compound of any one of aspects 8-15, wherein R²        is substituted with —C(O)—C(R³)═CR⁴(R⁵).    -   Aspect 17. The compound of any one of aspects 14-16, wherein R³        is H.    -   Aspect 18. The compound of any one of aspects 14-16, wherein R³        is —CN.    -   Aspect 19. The compound of any one of aspects 14-16, wherein R³        is F or Cl.    -   Aspect 20. The compound of any one of aspects 14-16, wherein R³        is C¹⁻⁶haloalkyl or C₁₋₆alkyl.    -   Aspect 21. The compound of any one of aspects 14-20, wherein one        of R⁴ and R⁵ is H.    -   Aspect 22. The compound of any one of aspects 14-20, wherein R⁴        is H and R⁵ is H.    -   Aspect 23. The compound of any one of aspects 14-21, wherein one        of R⁴ and R⁵ is halogen; —C₁₋₆alkyl; —OC₁₋₆alkyl;        —C₁₋₆alk-O—C₁₋₆alkyl; —C₀₋₆alk-C₃₋₆cycloalkyl optionally        substituted with C₁₋₆alkyl; or —C₁₋₆alk-OH.    -   Aspect 24. The compound of any one of aspects 14-21, wherein one        of R⁴ and R⁵ is —C₀₋₆alk-NR⁶R⁷, —C₁₋₆alk-NR⁶R⁷, or        —C₁₋₆alk-NH—C₀₋₆alk-O—C₁₋₆alkyl.    -   Aspect 25. The compound of any one of aspects 14-21, wherein one        of R⁴ and R⁵ is —C₀₋₆alk-heterocycloalkyl or        —C₁₋₆alk-heterocycloalkyl optionally substituted with        —C(O)C₁₋₆alkyl.    -   Aspect 26. The compound of any one of aspects 14-20, wherein one        of R⁴ and R⁵ is or —NHC(O)—C₁₋₆alkyl.    -   Aspect 27. The compound of any one of aspects 14-20, wherein one        of R⁴ and R⁵ is —C₁₋₆alk-NHSO₂—C₁₋₆alkyl or        —C₁₋₆alk-SO₂—C₁₋₆alkyl.    -   Aspect 28. The compound of any one of the preceding aspects,        wherein A is a bond, naphthalenyl, or benzo[d][1,3]dioxolyl.    -   Aspect 29. The compound of any one of aspects 1-27, wherein A is        phenyl.    -   Aspect 30. The compound of any one of aspects 1-27, wherein A is        pyridyl.    -   Aspect 31. The compound of any one of aspects 1-27, wherein A is        pyrimidinyl.    -   Aspect 32. The compound of any one of aspects 1-27, wherein A is        pyrazinyl.    -   Aspect 33. The compound of any one of aspects 1-27, wherein A is        pyridazinyl.    -   Aspect 34. The compound of any one of aspects 29-33, wherein A        is substituted with 1 or 2 substitutents.    -   Aspect 35. The compound of aspect 34, wherein A is substituted        with —C₁₋₆alkyl, preferably —CH₃.    -   Aspect 36. The compound of any one of the preceding aspects,        wherein E is O.    -   Aspect 37. The compound of any one of aspects 1-35, wherein E is        a bond.    -   Aspect 38. The compound of any one of aspects 1-35, wherein E is        —C(O)—NH—, —CH₂—, or —CH₂O—.    -   Aspect 39. The compound of any one of aspects 1-38, wherein G is        H.    -   Aspect 40. The compound of any one of aspects 1-38, wherein G is        —C₁₋₆alkyl; —C₁₋₆haloalkyl; —C₁₋₆alk-O—C₁₋₆alkyl; or        —C₃₋₆cycloalkyl.    -   Aspect 41. The compound of any one of aspects 1-38, wherein G is        —C₁₋₆alkyl or —C₃₋₆cycloalkyl.    -   Aspect 42. The compound of any one of aspects 1-38, wherein G is        —NR⁶R⁷ or —OH.    -   Aspect 43. The compound of any one of aspects 1-38, wherein G is        -heterocycloalkyl that contains an oxygen heteroatom.    -   Aspect 44. The compound of any one of aspects 1-38, wherein G is        —SO₂C₁₋₆alkyl.    -   Aspect 45. The compound of any one of aspects 1-38, wherein G is        -phenyl.    -   Aspect 46. The compound of any one of aspects 1-38, wherein G is        -pyridyl.    -   Aspect 47. The compound of any one of aspects 1-38, wherein G is        -pyrimidinyl or pyridazinyl.    -   Aspect 48. The compound of any one of aspects 1-38, wherein G is        -benzofuranyl or -thiophenyl.    -   Aspect 49. The compound of any one of aspects 1-38, wherein G is        -phenyl-CH₂—O-phenyl.    -   Aspect 50. The compound of any one of aspects 45-49, wherein G        is substituted with 1 or 2 substitutents.    -   Aspect 51. The compound of aspect 50, wherein G is substituted        with halogen.    -   Aspect 52. The compound of aspect 50 or aspect 51, wherein G is        substituted with —C₁₋₆alkyl; —C₁₋₆haloalkyl; —OC₁₋₆haloalkyl;        —C₃₋₆cycloalkyl; —OC₁₋₆alkyl; —C₁₋₆alk-O—C₁₋₆alkyl; or        —C(O)—C₁₋₆alkyl.    -   Aspect 53. The compound of any one of aspects 50-52, wherein G        is substituted with —CN.    -   Aspect 54. The compound of any one of aspects 50-53, wherein G        is substituted with —OH.    -   Aspect 55. The compound of any one of aspects 50-54, wherein G        is substituted with —C(O)—NR⁶R⁷.    -   Aspect 56. The compound of any one of aspects 1-27, wherein        A-E-G is -phenyl-O-phenyl or -pyridyl-O-phenyl.    -   Aspect 57. The compound of aspect 56, wherein A-E-G is

-   -   Aspect 58. The compound of aspect 1, wherein R¹ is H; R² is        C₀alk-piperidinyl substituted with 1 or 2 substituents wherein        one of the substituents is —C(O)—C(R³)═CR⁴(R⁵), wherein R³, R⁴,        and R⁵ are each H; A is phenyl or pyridyl substituted with —CH₃;        E is O; and G is phenyl.    -   Aspect 59. The compound of aspect 58, wherein R² is substituted        with 1 substituent that is —C(O)—C(R³)═CR⁴(R⁵).    -   Aspect 60. The compound of aspect 58 or aspect 59, wherein A-E-G        is

-   -   Aspect 61. The compound of any one of aspects 58, 59, or 60,        wherein the compound of formula I is

-   -   Aspect 62. The compound of any one of the preceding aspects that        is a pharmaceutically acceptable salt.    -   Aspect 63. A pharmaceutical composition comprising a compound of        any one of aspects 1-61, or a pharmaceutically acceptable salt        thereof, and a pharmaceutically acceptable excipient.    -   Aspect 64. A method of inhibiting Bruton's tyrosine kinase        comprising contacting the kinase with a compound of any one of        aspects 1-61.    -   Aspect 65. A method of treating cancer in a patient comprising        administering to the patient a compound of any one of aspects        1-61, or a pharmaceutically acceptable salt thereof.    -   Aspect 66. The method of aspect 65, wherein the cancer is mantle        cell lymphoma, chronic lymphocytic leukemia, macroglobulinemia,        or multiple myeloma.    -   Aspect 67. A method of treating systemic lupus erythematosus in        a patient comprising administering to the patient a compound of        any one of aspects 1-61, or a pharmaceutically acceptable salt        thereof.    -   Aspect 68. A method of treating a pemphigus disorder or a        pemphigoid disorder in a patient comprising administering to the        patient a compound of any one of aspects 1-61, or a        pharmaceutically acceptable salt thereof.    -   Aspect 69. A method of treating rheumatoid arthritis in a        patient comprising administering to the patient a compound of        any one of aspects 1-61, or a pharmaceutically acceptable salt        thereof.    -   Aspect 70. A method of making a compound of any one of aspects        1-61, or a pharmaceutically acceptable salt thereof.    -   Aspect 71. A compound as recited in Table 1.

1. A compound of Formula (I′), and pharmaceutically acceptable salts,stereoisomers, isotopes, N-oxides, or solvates thereof,

wherein R¹ is H or C₁₋₆alkyl; R² is selected from the group consistingof: C₀₋₂alk-piperidinyl; C₀₋₂alk-pyrrolidinyl; oxazepanyl; azetidinyl;azepanyl; quinuclidinyl; C₂alk-imidazolidinyl; C₂alk-piperazinyl;C₂alk-morpholinyl; tetrahydropyranyl; and C₀₋₁alk-tetrahydrofuranyl;wherein the R² is optionally substituted with 1, 2, or 3 substituentseach independently selected from the group consisting of:(C═O)—C(R³)═CR⁴(R⁵); oxo; halogen; OH; NH₂; CN; C₁₋₆alkyl; C₁₋₆alk-OH;OC₁₋₆alkyl; C₁₋₆haloalkyl; C₃₋₆cycloalkyl; SO₂C₁₋₆alkyl;SO₂—C₂₋₆alkenyl; C₁₋₂alk-aryl; (C═O)H; (C═O)C₁₋₆alkyl;(C═O)C₁₋₆haloalkyl; (C═O)—C₂₋₆alkenyl; (C═O)—C₂₋₆alkynyl;(C═O)C₃₋₆cycloalkyl; (C═O)-phenyl; (C═O)-imidazolyl; (C═O)—C₁₋₆alkCN;(C═O)—C₁₋₆alk-OH; (C═O)—C₁₋₆alk-SO₂C₁₋₆alkyl; (C═O)—C₁₋₆alk-NR⁶R⁷;(C═O)—C₁₋₆alk-O—C₁₋₆alkyl wherein the —C₁₋₆alk- is optionallysubstituted with OH, OC₁₋₆alkyl, or NR⁶R⁷; (C═O)C₀₋₁alk-heterocycloalkylwherein the -alk- is optionally substituted with oxo and theheterocycloalkyl is optionally substituted with C₁₋₆alkyl; andNH(C═O)—C(R³)═CR⁴(R⁵); wherein R³ is selected from the group consistingof: H, CN, halogen, C₁₋₆haloalkyl, and C₁₋₆alkyl; R⁴ and R⁵ are eachindependently selected from the group consisting of: H; halogen;C₁₋₆alkyl; CH₂OH; C₁₋₆alk-OC₁₋₆alkyl; OC₁₋₆alkyl; C₁₋₄alk-NR⁶R⁷;C₃₆cycloalkyl substituted with NH₂ or CH₃; oxetanyl substituted withCH₃; 1-acetylpyrrolidin-2-yl; CH₂-pyrrolidinyl; CH₂-piperidinyl;C(CH₃)₂-piperidinyl; CH₂-morpholinyl; C(CH₃)₂-morpholinyl;CH₂-(4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl;C(CH₃)₂NH(CH₂CH₂OCH₃); CH₂SO₂CH₃; CH₂NHSO₂CH₃; NH(C═O)C₁₋₆alkyl; andlinker-PEG-Biotin; and R⁶ and R⁷ are each independently selected fromthe group consisting of: H, C₁₋₆alkyl, cyclopropyl, (C═O)H, and CN; A isselected from the group consisting of: a bond, phenyl; naphthalenyl,pyridyl; pyrimidinyl; pyrazinyl; pyridazinyl; benzothiophenyl; andpyrazolyl; wherein the A is optionally substituted with 1, 2, or 3substituents each independently selected from the group consisting of:C₁₋₆alkyl, halogen, OC₁₋₆alkyl, (C═O)C₁₋₆alkyl, and C₁₋₆haloalkyl; E isselected from the group consisting of: —O—, a bond, (C═O)—NH, CH₂, andCH₂—O; and G is selected from the group consisting of: H, C₁₋₆alkyl;C₁₋₆haloalkyl; C₁₋₆alk-OC₁₋₆alkyl; NR⁶R⁷; SO₂C₁₋₆alkyl; OH;C₃₋₆cycloalkyl; phenyl; thiophenyl; pyrimidinyl; pyridyl; pyridazinyl;benzofuranyl; heterocycloalkyl that contains an oxygen heteroatom;phenyl-CH₂—O-phenyl; wherein the phenyl, thiophenyl, pyrimidinyl,pyridyl, pyridazinyl, or benzofuranyl is optionally substituted with 1,2, or 3 substituents each independently selected from the groupconsisting of: halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, OC₁₋₆haloalkyl,OC₁₋₆alkyl, OC₁₋₆alkyl-OC₁₋₆alkyl, C₃₋₆cycloalkyl, CN, OH, NH₂, N(CH₃)₂,C₁-6alk-OC₁₋₆alkyl, SO₂C₁₋₆alkyl, (C═O)—NR⁶R⁷, SF₅, and (C═O)C₁₋₆alkyl;and stereoisomers or isotopic variants thereof; and pharmaceuticallyacceptable salts thereof.
 2. The compound of claim 1, wherein R¹ is H.3. The compound of claim 1, wherein R² is piperidinyl,CH₂CH₂-piperidinyl, pyrrolidinyl, CH₂-pyrrolidinyl, orCH₂CH₂-pyrrolidinyl. 4.-13. (canceled)
 14. The compound of claim 1,wherein R² is substituted with (C═O)—C(R³)═CR⁴(R⁵).
 15. The compound ofclaim 14, wherein R³ is H. 16.-19. (canceled)
 20. The compound of claim1, wherein R⁴ is H and R⁵ is H. 21.-26. (canceled)
 27. The compound ofclaim 1, wherein A is pyridyl. 28.-30. (canceled)
 31. The compound ofclaim 1, wherein A is substituted with CH₃.
 32. The compound of claim 1,wherein E is O. 33.-38. (canceled)
 39. The compound of claim 1, whereinG is phenyl.
 40. The compound claim 1, wherein G is pyridyl. 41.-51.(canceled)
 52. The compound of claim 1, wherein R¹ is H; R² ispiperidinyl substituted with 1 or 2 substituents wherein one of thesubstituents is (C═O)—C(R³)═CR⁴(R⁵), wherein R³, R⁴, and R⁵ are each H;A is phenyl or pyridyl substituted with CH₃; E is O; and G is phenyl.53. (canceled)
 54. The compound of claim 1, wherein the compound isselected from the group consisting of:N-((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(3-fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-fluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(benzofuran-7-yloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(2,6-difluorophenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5, 8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(2-ethylphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-fluoro-6-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(benzofuran-7-yloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(*S)-2-Methyl-4-phenoxyphenyl)-N(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S,E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Chioroacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-1Acryloyl-4-fluoropyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo,4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,EZ)—N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-Hydroxybut-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(4-Cyano-1,4-oxazepan-6-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(cyclohexyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1Cyanopiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(*S)-2-Methyl-4-phenoxyphenyl)N-(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(cyclohexyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-13C-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(But-2-ynoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-4-methyl-4-morpholinopent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-fluoro-6-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(1-propioloylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Fluoroacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Fluoroacryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-cyclopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(2,6-Difluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(But-2-ynoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(2-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-ethyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-4-methyl-4-(tetrahydro-2H-pyran-4-yl)pent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(2,6-difluorophenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-ethoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2,6-difluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(Benzofuran-7-yloxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(3-Methoxypropanoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Ethylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(3-Hydroxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(2-ethylphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2,3-dimethyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-fluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2,6-dimethyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pentafluorothio)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-Tetrahydro-2H-pyran-3-y5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxylate;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2,4-dimethylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(3-methoxypropanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1,6-Dimethylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Isopropylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-4-Fluoro-1-(3-methoxypropanoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Methoxyacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Cyanoazepan-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(3-Hydroxypropanoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Isopropylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1,6-Dimethylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Fluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Acryloylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-13C-Acryloylpiperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-((R)-2-Amino-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-4-methyl-4-morpholinopent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(2-hydroxyacetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(2-methoxyacetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,Z)—N-(1-(But-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Isopropylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-ethyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-((S)-2-Amino-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridazin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-((S)-2-Hydroxy-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Hydroxyacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((S)-1-methylpyrrolidine-3-carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-(3-hydroxypropanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(4-Methyl-1,4-oxazepan-6-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(3-(Dimethylamino)propanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((S)-pyrrolidine-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-4-Fluoro-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Chloro-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,Z)—N-(1-(2-Cyano-4-(dimethylamino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Fluoro-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(oxetane-3-carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-N-methyl-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-5-Fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-4-Hydroxy-1-(3-methoxypropanoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Cyano-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Ethylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-((S)-2,3-Dimethoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-((R)-2-Hydroxy-3-methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(2-(trifluoromethyl)acryloyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((R)-1-methylpyrrolidine-3-carbonyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-(o-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Cyclopropylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-4-methyl-4-(piperidin-1-yl)pent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Aminoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-4-(cyclopropylamino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-((6S)-6-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-4-Fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R)-1-(3-Methoxybutanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-((S)-3-Methoxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(2-Ethoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R)-1-(3-Methoxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-5-Fluoro-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propioloylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-(1-methyl-6-oxopiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(3-Aminopropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-5-Fluoro-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1,3-Dimethylpiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(2-oxopiperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-5-fluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-5-Hydroxy-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(2-Ethylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(quinuclidin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-(3-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-((6R)-6-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(5,5-Difluoropiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2,6-difluoro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;13C—(R,Z)—N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;13C—(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(cyclohexyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-5-Hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Methylpiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-cyclopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-4-Fluoro-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazepan-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(3-Methoxy-2,2-dimethylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Cyanoazepan-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-((R)-2,3-Dimethoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((R)-pyrrolidine-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-ethoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-fluorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,Z)—N-(1-(4-Amino-2-cyano-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(3-(1-Aminocyclopropyl)-2-cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-5-Hydroxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((R)-tetrahydrofuran-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(3-Cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-4-Hydroxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(2-Cyclopropylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1,2-Dimethylpiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Methacryloylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-(Cyclopropanecarbonyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazepan-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((S)-tetrahydrofuran-3-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-4-Methoxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-(m-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-4-Methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-4-(ethylamino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Cyclopropylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(3-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Fluoro-4-phenoxyphenyl)-N-(1-(3-methoxypropanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(2-(2-oxoimidazolidin-1-yl)ethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-4-Fluoropyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(tetrahydro-2H-pyran-4-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(2-Hydroxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(3-Ethoxyacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Fluoro-6-methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(2-Isopropylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-5-Methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-methylbut-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(3-(Methoxymethyl)phenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-(2-(trifluoromethoxy)phenoxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,Z)—N-(1-(3-Cyclopropyl-2-fluoroacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Cyclopropylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,EZ)—N-(1-(2-Cyano-3-methoxyacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(*S)-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-(2-cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,EZ)—N-(1-(2-Cyano-4-((2-methoxyethyl)amino)-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2,6-Difluoro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-4-Hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N1-((E)-4-(3-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)-N5-(15-oxo-19-((3aS,4R,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)glutaramide;(R,E)-N-(1-(2-Cyano-4-methyl-4-(methylamino)pent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-(2-cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)azetidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-4-Hydroxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-(2-(trifluoromethyl)phenoxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-4-Hydroxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-4-Methoxy-1-methylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-4-Methoxypyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-(3-Methoxypropanoyl)azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-methylpent-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylazetidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(Cyclohexyloxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Ethylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(Azetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-fluorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-chlorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-phenyl-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-(2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-5-Methoxy-1-methylpiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,Z)—N-(1-(2-Fluorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Methyl-5-oxopyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Fluoro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pentafluorothio)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(2-Methyl-4-phenoxyphenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-5-Hydroxy-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-5-Methoxypiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-2-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(p-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(5,5-Difluoro-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Isopropylazetidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4,4-Dimethylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-(2-morpholinoethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-2-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,Z)—N-(1-(2-Chlorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenoxy-2-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(m-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Chloro-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2,3-Dimethyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-((1-methylpyrrolidin-3-yl)methyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(2-Isopropoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Cyclobutoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-N-((1-methylpyrrolidin-2-yl)methyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(3,5-Difluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-(p-tolyloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(2-Methyl-4-phenoxyphenyl)-N-(2-(3-methylmorpholino)ethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-(pyridin-3-yloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-chlorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(4-Fluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(2-(3-methylmorpholino)ethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(Cyclopentyloxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-fluorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(2,4-Difluorophenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(5-Fluoro-2-methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2,4-dimethylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(5-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-(pyridin-2-yloxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(5-Fluoro-2-methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-Benzyl-2-oxoazepan-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-2-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(6-phenoxypyridazin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-5-Methoxy-1-methylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,EZ)—N-(1-(3-Cyclopropyl-2-(trifluoromethyl)acryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-(2-morpholino-2-oxoethyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2,6-Dimethyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(3-Hydroxypropanoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Ethylpiperidin-3-yl)-5-(4-(2-isopropylphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(5-chlorobenzo[d][1,3]dioxol-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Cyclopropoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxy-2-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(2-Carbamoylphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-2-(piperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;(R)-6-Methyl-4-oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Cyanopiperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3,5-Dichlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-Methyl-5-(2-methyl-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Isopropoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Ethoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(tert-butyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Chlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-phenyl-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-Methyl-5-(2-methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Methoxy-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-N-(piperidin-3-yl)-5-(4-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Methoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*R)-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-([1,1′-Biphenyl]-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*R)-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(trifluoromethyl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-isopropyl-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3,4-dichlorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-chloro-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(3-Methoxy-3-methylbutanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,Z)—N-(1-(3-Acetamidoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Chloroacryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(vinylsulfonyl)pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-trideuteriomethylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(vinylsulfonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylsulfonyl)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-N-(1-(trideuteriomethyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-(2,3,4,5,6-pentadeuteriophenoxy)phenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-Aminobut-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylsulfonamido)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-(Dimethylamino)acetyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyanobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-((S)-Azetidine-2-carbonyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,Z)—N-(1-(2-Fluoro-4-(methylamino)but-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(2-(pyrrolidin-1-yl)acetyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-2-(((1-Acryloylpiperidin-3-yl)amino)methyl)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Aminoacetyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(2-(piperidin-1-yl)acetyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(2-morpholinoacetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Chloroacetyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Chloroacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(thiophen-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(3-Cyclopropyl-2-methylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,EZ)—N-(1-(2-Chloro-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-morpholinobut-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(benzo[b]thiophen-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Isopropoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-N-(piperidin-3-yl)-5-(4-(thiophen-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenoxybenzyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Methylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxybenzyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(Benzo[b]thiophen-5-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-(trifluoromethoxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-N-(piperidin-3-yl)-5-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(naphthalen-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(1-benzyl-1H-pyrazol-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-benzylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-([1,1′-Biphenyl]-4-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-(Dimethylamino)acetyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-(Dimethylamino)acetyl)pyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-([1,1′-Biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(benzo[b]thiophen-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Benzylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-((4*S)-2-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-((4*S)-2-methylpiperidin-4-yl)-4-oxo-4,5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-((4*R)-2-methylpiperidin-4-yl)-4-oxo-4,5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(*R)-(2-Methyl-4-phenoxyphenyl)-N-((4*R)-2-methylpiperidin-4-yl)-4-oxo-4,5dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(4-(Hydroxymethyl)tetrahydro-2H-pyran-4-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1(2-Chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1(2-Chloro-3-methylbut-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-N-methyl-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-N-methyl-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-isopropyl-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Isopropyl-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Isopropyl-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,*Z)—N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,*Z)—N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,*E)-N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,*E)-N-(1-(2-Cyano-4-methoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((1-Acryloylpyrrolidin-3-yl)methyl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;4-Oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-ylmethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-cyclobutoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-cyclobutoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;4-Oxo-N-(2-oxopiperidin-3-yl)-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Chloro-4-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Methyl-3-(trifluoromethyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;4-Oxo-5-(4-phenoxyphenyl)-N-((tetrahydrofuran-2-yl)methyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-4-oxo-5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-4-Hydroxypyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Benzylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-5-(3-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-5-Methoxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-5-Methoxypiperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(*S)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(*S)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(*R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(*R)-5-(*R)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(5-oxopyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,*E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,*E)-N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,*Z)—N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,*Z)—N-(1-(But-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,*Z)—N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,*E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,*Z)—N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,*E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*R)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(4-Cyano-1,4-oxazepan-6-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)pyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(3-(methylsulfonyl)propanoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Methoxyacetyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Acryloylazetidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-methyl-5-phenoxypyridin-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′,3′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-1-Acryloyl-5-fluoropiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3′-fluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-cyclobutoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N(1-(4-Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3′-chloro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-5-(*S)-2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,EZ)—N-(1(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′-chloro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-Aminobut-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-benzylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3′-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclohexylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-Aminobut-2-enoyl)pyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4′-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-Hydroxybut-2-enoyl)pyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(*S)-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((S)-2-(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-phenylpyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyrazin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-isopropylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(vinylsulfonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-acryloylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-(4-(methylsulfonamido)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-propylphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclobutylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-N-(1-trideuteriomethylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenylpyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(pyridin-3-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(Ethylsulfonyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(pyridin-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Isopropylpiperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-1-Acryloyl-4-fluoropyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)pyrrolidine-3-carboxamide;(R)-1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)pyrrolidine-3-carboxamide;(R)—N-(1-(2-(Methylamino)acetyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-((S)-3-Hydroxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-1-Acryloyl-4-methoxypyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,Z)—N-(1-(4-Amino-2-fluorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,Z)—N-(1-(4-Amino-2-chlorobut-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3′-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2′-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((E)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoyl)pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2-phenoxypyrimidin-5-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(3-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(cyclohexyloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(cycloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-((R)-3-Hydroxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-isopropoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Acetylphenyl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-cyclopropylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-((R)-3-Methoxy-2-methylpropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(2-(dimethylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(cis)-1-Acryloyl-3-hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Methoxyacetyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Chloro-4-phenoxyphenyl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;4-Oxo-N-(6-oxopiperidin-3-yl)-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-4-Fluoropyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4′-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Chloro-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acetylpiperidin-3-yl)-5-(3-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-chloro-4-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-5-(2-phenylpyridin-4-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-5-Hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-methylpyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4S)-4-Methoxypyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5R)-1-Acryloyl-5-hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-cyclobutylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Cyanopiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(3-Methoxypropanoyl)piperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Cyanopiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Methyl-5-phenoxypyridin-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-N-(1-(4-Hydroxybut-2-enoyl)piperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-(3-Methoxypropanoyl)piperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-3-amino-4-((3-cyclobutoxyphenyl)amino)thieno[2,3-b]pyridine-2-carboxamide;(R)-5-([1,1′-Biphenyl]-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;2-((1-Acryloylpiperidin-3-yl)amino)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;(R)-5-([1,1′-Biphenyl]-3-yl)-N-(1-(2-(methylamino)acetyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-5-(2-phenylpyridin-4-yl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Cyclobutylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenylpyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Cyclobutoxy-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;2-((1-Acryloylpiperidin-4-yl)amino)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-3-(trifluoromethyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(4-Isopropoxy-2-methylphenyl)-4-oxo-N—((R)-1-((E)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-cyclobutoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-5-(4-phenylpyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(3R,5R)-tert-Butyl3-hydroxy-5-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(oxetan-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-(Cyclopentyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(trans-3-Hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-(Cyclohexyloxy)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;trans-tert-Butyl3-hydroxy-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;(R)-4-Oxo-5-(5-phenylpyridin-3-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(trifluoromethoxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Cyclobutoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(pyridin-2-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-5-(6-phenylpyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-(trifluoromethoxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(3S,4S)-tert-Butyl3-fluoro-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidine-1-carboxylate;(R)-5-(4-Cyclobutoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;tert-Butyl4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;(R)-tert-Butyl3-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;(R)-5-(3-Cyclohexylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Isopropylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(pyridin-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(oxetan-3-yl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isopropoxy-3-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Cyclobutylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Isopropoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(tert-butyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(3S,4S)-tert-Butyl3-methoxy-4-(4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)pyrrolidine-1-carboxylate;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(5-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(tert-butylsulfonyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Hydroxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Acetylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,4R)-1-Acryloyl-4-hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Methyl-5-phenoxypyrazin-2-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-methyl-5-phenoxypyrazin-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,4R)-4-Hydroxypiperidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(cis-3-Hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;4-Oxo-N-(2-oxopyrrolidin-3-yl)-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(R)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(4-methyl-6-phenoxypyrimidin-5-yl)-4-oxo-4,5-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(4-methyl-2-phenoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyrimidin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(cis-4-Acrylamidotetrahydrofuran-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2′,3′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-1-Acryloyl-5-hydroxypiperidin-3-yl)-5-(2′,3′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(3-methyl-2-phenylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-cyclohexylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenylpyridazin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3R,5S)-1-Acryloyl-5-methoxypiperidin-3-yl)-5-(2′,3′-difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(6-phenoxypyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1 ((*E)-3-((S)-1-Acetylpyrrolidin-2-yl)-2-cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1Acryloylpiperidin-3-yl)-5-(*S)-(6-cyclobutoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-((E)-3-((R)-1-Acetylpyrrolidin-2-yl)-2-cyanoacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((E)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenylpyrimidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-chloro-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-isobutylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo,4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-cyclopentylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(cyclopentyloxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(5-methyl-2-phenylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(2-isopropoxyethoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-isopropylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-phenoxypyrazin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-cyclobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-([2,3′-Bipyridin]-4-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(4-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(3-Chloro-4-phenoxyphenyl)-N-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-cyclobutoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(3-isopropylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2′,3′-Difluoro-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((1RS,2RS)-2-Aminocyclopentyl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(3-(tetrahydro-2H-pyran-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-([2,2′-Bipyridin]-4-yl)-N-(1-acryloylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2′,3′-Difluoro-[1,1′-biphenyl]-3-yl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(trans-1-Acryloyl-3-hydroxypiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(Methylglycyl)piperidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(4-Methyl-2-phenoxypyrimidin-5-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3S,4R)-1-Acryloyl-4-hydroxypyrrolidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-5-(5-phenoxypyrimidin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Cyclopentylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Isobutylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-5-(6-phenylpyrimidin-4-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(4-methyl-2-phenoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Methyl-[1,1′-biphenyl]-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-cyclobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Isopropylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*R)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(5-Methyl-2-phenylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(2-Isopropoxyethoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Cyclohexylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-isopropoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(3-Methyl-2-phenylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-phenylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-6-phenylpyridin-4-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-cyclobutoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(3-methyl-2-phenylpyridin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(tetrahydro-2H-pyran-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-tert-Butyl3-(4-oxo-5-(3-(tetrahydro-2H-pyran-4-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;(R)-4-Oxo-5-(6-phenylpyridazin-4-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-5-(6-phenoxypyridin-3-yl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-tert-Butyl3-(5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidine-1-carboxylate;(R)-5-(6-Cyclobutoxypyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-((3*S,4*R)-4-Acrylamidotetrahydrofuran-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-methyl-2-phenoxypyrimidin-5-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(2-phenoxypyrimidin-5-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-phenoxypyrimidin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-isobutylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenylpyridazin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(*3R,*4S)-4-Acylamidotetrahydrofuran-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isopropoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Isobutylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-5-(5-phenylpyridazin-3-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isopropoxy-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(6-Isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*R)-(6-Isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(6-Cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*R)-(6-(Cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(4-Methyl-2-phenoxypyrimidin-5-yl)-4-oxo-N-(piperidin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(6-isobutyl-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(6-Isobutyl-4-methylpyridin-3-yl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((6-methylpyridin-2-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-((6-methylpyridin-2-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-(cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(5-(2-fluorophenoxy)pyridin-2-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-isobutoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N1-(15-Oxo-19-((3aR,4R,6aS)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)-N5-((E)-4-oxo-4-(3-(4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamido)piperidin-1-yl)but-2-en-1-yl)glutaramide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,EZ)—N-(1-(2-Cyano-3-(3-methyloxetan-3-yl)acryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-((6-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-((5-methylpyridin-2-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isopropoxy-4-methypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutyl-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(2-Methyl-6-phenoxypyridin-3-yl)-4-oxo-N-(tetrahydrofuran-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(6-Isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;2-(4-Acryloylpiperazin-1-yl)-5-(2-methyl-4-phenoxyphenyl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;(R)-5-(*S)-(6-(Cyclopentyloxy)-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(6-Isobutoxy-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acetylpiperidin-3-yl)-5-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-1-(2-Cyano-3-cyclopropylacryloyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;1-Cyano-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)-1-propionylpiperidine-4-carboxamide;(R)-5-(*R)-(6-Isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-N-(1-propionylpiperidin-3-yl)-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acetylpiperidin-3-yl)-4-oxo-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acetylpiperidin-3-yl)-5-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acetylpiperidin-3-yl)-4-oxo-5-(4-(pyridazin-3-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(6-isobutyl-2-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-1-(2-Cyano-4,4-dimethylpent-2-enoyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;1-(2-Cyanoacetyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)-1-propionylpiperidine-3-carboxamide;1-(2-Cyanoacetyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;1-Acryloyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;1-Ethyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;1-Cyano-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;1-Methyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-2-(4-methylpiperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;(E)-4,4-Dimethyl-2-(4-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperazine-1-carbonyl)pent-2-enenitrile;4-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperazine-1-carbonitrile;5-(2-Methyl-4-phenoxyphenyl)-2-(4-propionylpiperazin-1-yl)-3H-1-thia-3,5,8-triazaacenaphthylen-4(5H)-one;N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-3-carboxamide;(E)-1-(2-Cyano-4,4-dimethylpent-2-enoyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;(E)-1-(2-Cyano-3-cyclopropylacryloyl)-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;1-Methyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;1-Ethyl-N-(5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;N-(5-(2-Methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylen-2-yl)piperidine-4-carboxamide;(R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(vinylsulfonyl)pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-fluoro-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Cyanopyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Cyanoacetyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(3-Methoxypropanoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2′,3′-difluoro-4-methyl-[1,1′-biphenyl]-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(4-(pyrrolidin-1-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((R)-2-(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N—((R)-1-((R)-Azetidine-2-carbonyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N—((R)-1-((S)-2-(methylamino)propanoyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-N-(1-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(4-(3-((2-Cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-5-(4-phenoxyphenyl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(4-(pyrrolidin-1-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Cyanopiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((R)-pyrrolidine-2-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-Formylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(4-(pyridin-2-yloxy)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Cyanopiperidin-3-yl)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Cyanopiperidin-4-yl)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Formylpiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acetylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Cyanopiperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-(2-Cyanoacetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N—((R)-1-((S)-pyrrolidine-2-carbonyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-(3-((2-cyanophenoxy)methyl)phenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(4-(2-methoxyphenoxy)-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-(4-(piperidin-1-yl)but-2-enoyl)piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-3-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-fluoro-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S,E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)pyrrolidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(3-Chloropropanoyl)piperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-(2-(Azetidin-1-yl)acetyl)piperidin-3-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;4-Oxo-5-(4-phenoxyphenyl)-N-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Methylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(4-(Dimethylamino)but-2-enoyl)piperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Benzoylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-5-(5-phenoxypyridin-2-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-4-oxo-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(4-(2-Methoxyphenoxy)-2-methylphenyl)-N-(1-methylpiperidin-4-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(Cyclopentyloxy)-2-methylphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Methylpiperidin-4-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(E)-N-(1-(2-Cyano-4,4-dimethylpent-2-enoyl)piperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-5-(6-phenoxypyridin-3-yl)-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Isopropoxy-2-methylphenyl)-N-(1-(2-(methylamino)acetyl)piperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-Acetylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Benzylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;4-Oxo-5-(4-phenoxyphenyl)-N-(piperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;4-Oxo-5-(4-phenoxyphenyl)-N-(2-(pyrrolidin-1-yl)ethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;4-Oxo-5-(4-phenoxyphenyl)-N-(2-(piperazin-1-yl)ethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-Acryloylpiperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-5-(2-Methyl-4-phenoxyphenyl)-N-(1-methylpiperidin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-Methylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;4-Oxo-5-(4-phenoxyphenyl)-N-(2-(piperidin-1-yl)ethyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(2-Morpholinoethyl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)-4-Oxo-5-(4-phenoxyphenyl)-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(2-(4-Methylpiperazin-1-yl)ethyl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acetylpiperidin-3-yl)-5-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-N-(piperidin-3-yl)-5-(3-(pyridin-3-yl)phenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-5-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(3-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-Benzoylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3,5-dichlorophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-4-oxo-5-(o-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(3-(dimethylamino)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N-(1-(2-Cyanoacetyl)piperidin-4-yl)-5-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S)—N-(1-Benzylpyrrolidin-3-yl)-4-oxo-5-(4-phenoxyphenyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(S,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(4-methoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;5-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(1-propionylpiperidin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-aminophenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(Dimethylamino)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-N-(piperidin-3-yl)-5-(m-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Chlorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-4-Oxo-N-(piperidin-3-yl)-5-(p-tolyl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-Fluorophenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(4-(tert-Butyl)phenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)-5-(*S)-(6-Isopropoxy-4-methylpyridin-3-yl)-4-oxo-N-(pyrrolidin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(6-isopropoxy-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-(1-methylcyclobutyl)acryloyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;N1-((E)-4-((R)-3-(1-(2-Methyl-6-phenoxypyridin-3-yl)-2-oxo-1,2,3,5-tetrahydrocyclopenta[de]quinazoline-4-carboxamido)piperidin-1-yl)-4-oxobut-2-en-1-yl)-N5-(15-oxo-19-((3aR,4R,6aS)-2-oxooctahydrocyclopenta[d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)glutaramide;(R,E)-N-(1-(2-Cyano-4-ethoxy-4-methylpent-2-enoyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R,E)-N-(1-(2-Cyano-3-cyclopropylacryloyl)piperidin-3-yl)-5-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*R)-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-(pyridin-2-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-((2-methylpyridin-3-yl)oxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*R)-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(2-methyl-4-(pyridazin-3-yloxy)phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-(pyridazin-3-yloxy)pyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-4-oxo-5-(5-(pyridazin-3-yloxy)pyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(2-methyl-6-(pyridazin-3-yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(2-methyl-6-(pyridazin-3-yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(4-methyl-6-(pyridazin-3-yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;and(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(4-methyl-6-(pyridazin-3-yloxy)pyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;and pharmaceutically acceptable salts thereof.
 55. The compound of claim1, wherein said compound is selected from the group consisting of:(R)—N-(1-Acryloylpiperidin-3-yl)-5-(R)-(4-isopropoxy-2-methylphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(6-phenoxypyridin-3-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(2-phenylpyridin-4-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyridin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(R)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(4-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-4-oxo-5-(5-phenoxypyrimidin-2-yl)-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;(R)—N-(1-Acryloylpiperidin-3-yl)-5-(*S)-(6-isobutyl-4-methylpyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide;and(R)—N-(1-Acryloylpyrrolidin-3-yl)-5-(*S)-(2-methyl-6-phenoxypyridin-3-yl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide,and pharmaceutically acceptable salts thereof.
 56. A pharmaceuticalcomposition comprising an effective amount of at least one compound ofclaim 1 and at least one pharmaceutically acceptable excipient.
 57. Apharmaceutical composition comprising an effective amount of at leastone compound of claim 54 and at least one pharmaceutically acceptableexcipient.
 58. A pharmaceutical composition comprising an effectiveamount of at least one compound of claim 55 and at least onepharmaceutically acceptable excipient.
 59. A method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by Bruton's tyrosine kinase activity, comprisingadministering to a subject in need of such treatment an effective amountof at least one compound claim
 1. 60.-63. (canceled)
 64. The method ofclaim 59, wherein the disease, disorder, or medical condition mediatedby Bruton's tyrosine kinase activity is rheumatoid arthritis.
 65. Amethod of making a compound of claim 1, or a pharmaceutically acceptablesalt thereof.
 66. A compound of claim 1 having the structure of Formula(II′), and stereoisomers, isotopic variants, and pharmaceuticallyacceptable salts thereof of Formula (II′);

wherein R^(a) is independently selected from the group consisting of: H,Cl, F, CH₃, and CF₃; n is 0-2; E is O; G is selected from the groupconsisting of: C₃₋₆cycloalkyl; oxetanyl; tetrahydrofuranyl;tetrahydropyranyl; benzofuran-7-yloxy; pyridyl; pyridyl substituted withCH₃; phenyl; phenyl substituted with one or two members independentlyselected from the group consisting of: halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, OH, OC₁₋₆alkyl, OC₁₋₆haloalkyl, CH₂OCH₃, (C═O)NH₂, andC₃₋₆cycloalkyl; and

Ring B is selected from the group consisting of: (a)

 wherein R^(b) is selected from the group consisting of: H; C₁₋₆alkyl,C₃₋₆cycloalkyl, (C═O)CH═CH₂, (C═O)CH₂CH₂OCH₃(C═O)CH₂CH₂SO₂CH₃, and

(b)

wherein R^(c) is selected from the group consisting of: H, C₁₋₆alkyl,CN, (C═O)C₁₃alkyl, (C═O)CH═CH₂, C₃₋₆cycloalkyl, (C═O)CH₂NH₂,(C═O)CH₂NH(CH₃), (C═O)CH₂N(CH₃)₂, (C═O)CH₂CN, CH₂-phenyl, (C═O)CH₂Cl,(C═O)CH═CHCH₂NH₂, (C═O)CH₂CH₂OCH₃, (C═O)CH═CHCH₂NH(CH₃),(C═O)CH═CHCH₂N(CH₃)₂, (C═O)CH═CHCH₂OH, (C═O)-phenyl, SO₂CH═CH₂,(C═O)CH₂CH₂SO₂CH₃,

R^(d) is selected from the group consisting of: H, F, OH, and OCH₃;R^(e) is H or C₁₋₆alkyl; (c)

wherein R^(d) is selected from the group consisting of: H, F, OH, andOCH₃; R^(f) is selected from the group consisting of:(C═O)—C(R³)═CR⁴(R⁵); H; C₁₆alkyl; CN; (C═O)C₁₋₃alkyl;(C═O)C₁₋₃haloalkyl; (C═O)C₂₋₆alkenyl; (C═O)C₂₋₆alkynyl; (C═O)(CH₂)₁₋₂OH;(C═O)(CH₂)₁₋₂OCH₃; (C═O)H; (C═O)(CH₂)₀₋₁CN; (C═O)CH₂NH₂;(C═O)(CH₂)₁₋₂NH(CH₃); (C═O)(CH₂)₁₋₂N(CH₃)₂; (C═O)CH(CH₃)NH(CH₃);(C═O)(CH₂)₁₋₂SO₂CH₃; (C═O)CH₂CH(CH₃)(OCH₃); (C═O)CH(CH₃)CH₂(OH);(C═O)CH(CH₃)CH₂(OCH₃); (C═O)C(CH₃)₂CH₂(OCH₃); (C═O)CH₂C(CH₃)₂(OCH₃);(C═O)CH(NH₂)CH₂(OCH₃); (C═O)CH(OCH₃)CH₂(OCH₃); (C═O)CH(OH)CH₂(OCH₃);C₃₋₆cycloalkyl; (C═O)(CH₂)₀₋₁azetidinyl; (C═O)oxetanyl;(C═O)tetrahydrofuranyl; (C═O)tetrahydropyranyl;(C═O)(CH₂)₀₋₁pyrrolidinyl, wherein said pyrrolidinyl is optionallysubstituted with CH₃; (C═O)(CH₂)₀₋₁piperidinyl;(C═O)(CH₂)₀₋₁morpholinyl; SO₂—C₂₋₆alkenyl; SO₂C₁₋₆alkyl; andlinker-PEG-Biotin; R³ is selected from the group consisting of: H, CN,halogen, C₁₋₆haloalkyl, and C₁₋₆alkyl; R⁴ and R⁵ are each independentlyselected from the group consisting of: H; halogen; C₁₋₆alkyl; CH₂OH;C₁₋₆alk-OC₁₋₆alkyl; OC₁₋₆alkyl; C₁₋₄alk-NR⁶R⁷; C₃₋₆cycloalkylsubstituted with NH₂ or CH₃; oxetanyl substituted with CH₃;1-acetylpyrrolidin-2-yl; CH₂-pyrrolidinyl; CH₂-piperidinyl;C(CH₃)₂-piperidinyl; CH₂-morpholinyl; C(CH₃)₂-morpholinyl;CH₂-(4aR,7aS)-tetrahydro-2H-[1,4]dioxino[2,3-c]pyrrol-6(3H)-yl;C(CH₃)₂NH(CH₂CH₂OCH₃); CH₂SO₂CH₃; CH₂NHSO₂CH₃; NH(C═O)C₁₋₆alkyl; andlinker-PEG-Biotin; and R⁶ and R⁷ are each independently selected fromthe group consisting of: H, C₁₋₆alkyl, C₃₋₆cycloalkyl, and CN; R^(g) isselected from the group consisting of: H, C₁₋₆alkyl, and CN; and (d)

and wherein R^(h) is selected from the group consisting of: H, CN, CH₃,and CH₂phenyl. 67.-68. (canceled)
 69. The compound of claim 1 having thestructure of Formula (III′), and stereoisomers, isotopic variants, andpharmaceutically acceptable salts of Formula (III′);

wherein G-A is selected from the group consisting of:

wherein G is phenyl; or phenyl substituted with one or two membersindependently selected from the group consisting of: halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₆cycloalkyl, pyridyl, oxetan-3-yl, andtetrahydro-2H-pyran-4-yl; R^(a) is H or CH₃; Ring B is selected from thegroup consisting of:

wherein R^(c) and R^(f) are independently selected from the groupconsisting of: H, C₁₋₆alkyl, (C═O)CH═CH₂, (C═O)CH₂NH(CH₃),(C═O)CH═CHCH₂N(CH₃)₂, and

and R^(d) is selected from the group consisting of: H, OH and OCH₃. 70.(canceled)
 71. The compound of claim 1 having the structure of Formula(IV′), and stereoisomers, isotopic variants, and pharmaceuticallyacceptable salts of Formula (IV′):

wherein G-E-A is selected from the group consisting of:

wherein G is selected from the group consisting of: C₁₋₆alkyl,C₃₋₆cycloalkyl, tetrahydro-2H-pyran-4-yl, pyridazin-3-yl, phenyl, andphenyl substituted with F; R^(a) is H or CH₃; Ring B is selected fromthe group consisting of:

R^(c) is selected from the group consisting of: H, C₁₋₆alkyl,(C═O)C₁₋₃alkyl, (C═O)CH═CH₂, (C═O)C₁₋₆haloalkyl,

and R^(j) is selected from the group consisting of: H, NH₂, andNH(C═O)CH═CH₂.
 72. (canceled)
 73. The compound of claim 1 having thestructure of Formula (V′), and stereoisomers, isotopic variants, andpharmaceutically acceptable salts of Formula (V′):

wherein G is selected from the group consisting of: C₁₋₆alkyl;C₁₋₆haloalkyl; phenyl; phenyl substituted with one or two membersindependently selected from the group consisting of: halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, OC₁₋₆alkyl, OC₁₋₆haloalkyl, (C═O)—C₁₋₆alkyl, SF₅, OH,NH₂, N(CH₃)₂, OCH₂CH₂OCH(CH₃)₂, and SO₂C₁₋₆alkyl; benzo[d][1,3]dioxolyloptionally substituted with Cl; 2-methylpyridin-3-yl;2-isopropylpyridin-4-yl; benzothiophenyl; napthalenyl; and2,2-difluorobenzo[d][1,3]dioxol-5-yl; Ring B is selected from the groupconsisting of:

wherein R^(c) and R^(f) are independently selected from the groupconsisting of: H, C₁₋₆alkyl, (C═O)C₁₋₃alkyl, (C═O)CH═CH₂, (C═O)CH₂NHCH₃,

and R^(d) is H or OH.